Healthy Volunteers
Conditions
Keywords
Dose escalation study, Safety, Pharmacodynamics, Pharmacokinetics, GSK3008356, Tolerability
Brief summary
This study is a phase I, randomized, placebo-controlled, double-blind (sponsor unblind), three part study. The primary objective of the study is to characterize the safety, and tolerability of GSK3008356 single dose, 14 daily repeat doses in healthy subjects and 28 daily repeat doses in obese subjects. The study has three parts. Part 1, will be a single and multiple-dose, dose-rising study in healthy subjects. Part 2, will be a 14-day, repeat-dose, dose-rising study in healthy subjects, and part 3 will be a 28-day, repeat-dose study in obese subjects. For Parts 1 and 2, data from prior doses cohorts will be available prior to escalation decisions. Data from Parts 1 and 2 will be available prior to initiation of the three parallel cohorts in Part 3. A dose escalation meeting will be held to review these data and document the decision to proceed as planned or make any alterations in dosing, if indicated. Part 1, Part 2 and Part 3 study will have approximately 88, 24 and 30 subjects, respectively.
Interventions
DRUGGSK3008356
This intervention is available as 0.5, 1, 5, and 25 mg white oral tablet. The formulation will be used to administer dose of 5 mg, 10 mg, 30 mg, 45 mg, 75 mg, 90 mg, 125 mg, 180 mg, 200 mg, and 250 mg total daily dose during the study.
DRUGPlacebo
This intervention is available as white oral tablet. The formulation will be used as a matching placebo for GSK3008356 during the study.
Sponsors
Nucleus Network Ltd
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 65 years of age inclusive, at the time of signing the informed consent. * For Part 1 and Part 2: Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. * For Part 3: Obese subjects may have chronic disease not specifically excluded and not requiring chronic medication for treatment and are otherwise healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Body weight \>=50 kilograms (kg) * For Part 1 and Part 2 body mass index (BMI) 19-25 kilogram per meter square (inclusive) * For Part 3 BMI \>=30 kilogram per meter square * Males or Females of non-childbearing potential as follows: Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until at least five half-lives of study medication after the last dose of study medication. 1. Vasectomy with documentation of azoospermia. 2. Male condom plus partner use of one of the following contraceptive options: Contraceptive subdermal implant; Intrauterine device or intrauterine system; Oral Contraceptive, either combined or progestogen alone; Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches * Males or Females of non-childbearing potential as follows: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin \[hCG\] test), not lactating, and the following condition applies: Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli-international units per milliliter (MlU/ml) and estradiol \< 40 picograms (pg) per ml (\<147 picomoles per liter (pmol/L) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will not be allowed. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Abnormal Findings in Physical Examinations | Up to Day 8 | A complete physical examination included assessment of the cardiovascular, respiratory, gastrointestinal, dermatologic and neurological systems, height, and weight. Height was measured and recorded only at screening. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight was recorded with the brief physical exam, but was not part of the brief physical exam. Number of participants with abnormal findings in physical examinations in Part 1 are presented. |
| Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | Up to Day 8 | Vital signs included systolic and diastolic blood pressure and pulse rate and were measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring. |
| Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | Up to Day 4 | Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 1 are presented. |
| Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | Day 1 | Continuous lead II cardiac telemetry or cardiac monitoring was performed on Day 1. Number of participants with clinically significant findings during cardiac monitoring in Part 1 are presented. |
| Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | Up to Day 8 | Hematology parameters included hematocrit, hemoglobin, platelets, white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cells (RBC) and reticulocytes. Clinical chemistry parameters included blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, uric acid, total protein, total and direct bilirubin, albumin, calcium, bile acids, chloride, creatinine, glucose (fasting/non-fasting), potassium, sodium and total carbon dioxide/bicarbonate. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine (WBC, RBC and casts) within 120 minutes of collection. |
| Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Up to Day 8 | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or is associated with liver injury and impaired liver function. |
| Part 2: Number of Participants With Abnormal Findings in Physical Examination | Up to Day 22 | A complete physical examination included assessment of the cardiovascular, respiratory, gastrointestinal, dermatologic and neurological systems, height, and weight. Height was measured and recorded only at screening. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight was recorded with the brief physical exam, but was not part of the brief physical exam. Number of participants with abnormal findings in physical examinations in Part 2 are presented. |
| Part 2: Number of Participants With Vital Signs of Potential Clinical Concern | Up to Day 22 | Vital signs included systolic and diastolic blood pressure and pulse and was measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring. |
| Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern | Up to Day 17 | Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QTcF. Number of participants with 12-lead ECG values of potential clinical concern in Part 2 are presented. |
| Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | Day 1 (Pre-dose to 4 hours post dose) | Continuous lead II cardiac telemetry or cardiac monitoring was performed on Day 1. Number of participants with clinically significant findings during cardiac monitoring in Part 2 are presented. |
| Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern | Up to Day 22 | Hematology parameters included hematocrit, hemoglobin, platelets, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cells and reticulocytes. Clinical chemistry parameters included blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, uric acid, total protein, total and direct bilirubin, albumin, calcium, bile acids, chloride, creatinine, glucose (fasting/non-fasting), potassium, sodium and total carbon dioxide/bicarbonate. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination (within 120 minutes of collection). |
| Part 2: Number of Participants With AE and SAE | Up to Day 22 | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or is associated with liver injury and impaired liver function. |
| Part 3: Number of Participants With Abnormal Findings in Physical Examination | Up to Day 36 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Number of Participants With Vital Signs of Potential Clinical Concern | Up to Day 36 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Number of Participants With 12-lead ECG Values of Potential Clinical Concern | Up to Day 31 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | Day 1 (Pre-dose to 4 hours post-dose) | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Number of Participants With Laboratory Values of Potential Clinical Concern | Up to Day 36 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Number of Participants With AE and SAE | Up to Day 36 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 3: AUC (0-tau) of GSK3008356 on Day 1 and Day 28 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Cmax of GSK3008356 on Day 1 and Day 28 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Tmax of GSK3008356 on Day 1 and Day 28 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: t1/2 of GSK3008356 on Day 28 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, 24, 36, 48, and 72 hours post-dose on Day 28 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Ae of GSK3008356 on Day 28 | Day 28 in each cohort | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose | Blood samples for pharmacokinetic (PK) analysis of GSK3008356 were collected at the indicated time points. |
| Part 3: Dose Proportionality of GSK3008356 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Observed Accumulation Ratio of GSK3008356 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Ctrough to Assess Steady State of GSK3008356 Following 28-day Repeat Dosing | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: Postprandial Triglyceride Levels Following 28-day Repeat Dosing of GSK3008356 in Obese Participants | Day -1, Day 1, and Day 28 in cohort 1, and Day 1, Day 2, and Day 28 in cohorts 2 and 3 | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 3: CLr of GSK3008356 on Day 28 | Day 28 in each cohort | Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted. |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post dose on Day 1 and 36, 48, and 72 hours post-dose | Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. |
| Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post dose on Day 1 and 36, 48, and 72 hours post-dose | Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. |
| Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours | Urine samples for PK analysis of GSK3008356 were collected at the indicated time points. |
| Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours | Urine samples for PK analysis of GSK3008356 were collected at the indicated time points. |
| Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC | Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose | Dose proportionality was assessed from the AUC (0 to t) and AUC (0 to inf) obtained from multiple cohorts in Part 1. The dose proportionality was assessed using a power model on logarithmic transformation of AUC with the logarithmic transformation of dose as the single covariate in the linear regression. Point estimates and 90% confidence interval are presented. |
| Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg vs. 200 mg After Single Dose Administration Based on Cmax | Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose | Dose proportionality was assessed from the Cmax obtained from multiple cohorts in Part 1. The dose proportionality was assessed using a power model on logarithmic transformation of Cmax, with the logarithmic transformation of dose as the single covariate in the linear regression. For Cmax, only a single dose group from Cohort 1 to Cohort 6 was considered since other cohorts are multiple dosing where Cmax is so different from that of single dose group. Data for Cohort A5 vs. Cohort A1 is presented, Point estimates and 90% confidence interval are presented. |
| Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1 at 1,2,3,4,5,6,7,8,9,12 hours post-dose | Preliminary pharmacodynamics of GSK3008356 was evaluated by assessing the postprandial triglyceride levels at the indicated time points. Corrected triglyceride value (Day 1) at each nominal sampling time point was defined as the corresponding post dose value by adding the following value: Part 1 Day 1 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 1 (1 hour + 2 hour)/2). Mean triglyceride levels are presented. |
| Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14 | Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose | Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. |
| Part 2: Cmax of GSK3008356 on Day 1 and Day 14 | Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose | Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. |
| Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose | Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. |
| Part 2: Ae of GSK3008356 on Day 14 | Pre-dose and 24 hours post-dose on Day 14 | Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study. |
| Part 2: CLr of GSK3008356 on Day 14 | Pre-dose and 24 hours post-dose on Day 14 | Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study. |
| Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC | Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose | Dose proportionality was assessed from Day 1 and Day 14 AUC (0 to tau) obtained from multiple cohorts in Part 2. The dose proportionality was assessed using a power model on logarithmic transformation of AUC, with the logarithmic transformation of dose as the single covariate in the linear regression. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. Point estimates and 90% confidence interval are presented. |
| Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on Cmax | Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post-dose | The dose proportionality was assessed using a power model on logarithmic transformation of Cmax, with the logarithmic transformation of dose as the single covariate in the linear regression. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. Point estimates and 90% confidence interval are presented for Day 1 and Day 14 of Part 2. |
| Part 2: Observed Accumulation Ratio of GSK3008356 | Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose | Observed accumulation ratio based on AUC(0- tau) is (Ro), and based on Cmax is (RCmax). Ro was calculated as the ratio \[AUC0-tau on the final day (Day 14)\]/\[ AUC0-tau on Day 1\] and Rcmax was calculated as the ratio \[Cmax on the final day (Day 14)\]/\[Cmax on Day 1\]. Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. |
| Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Pre-dose on Days 2, 4, 5, 6, 12, 13, 14 and the 24 hours post-dose on Day 14 | Ctrough is the observed concentration at the end of a dosing interval, immediately before next administration. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. |
| Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1 (1, 2, 3, 4, 5, 6, 7, 8, 9 and 12 hours post-dose) and Day 14 (1, 2, 3, 4, 5, 6, 7, 8, 9 and 12 hours post-dose) | Preliminary pharmacodynamics of GSK3008356 was evaluated by assessing the postprandial triglyceride levels at the indicated time points. Corrected TG value (Day 1 and Day 14) at each nominal sampling time point defined as the corresponding post dose value by adding the following value: Part 2 Day 1 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 1 (1 hour + 2 hour)/2); Part 2 Day 14 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 14 (1 hour + 2 hour)/2). Mean triglyceride levels are presented. |
Countries
Australia
Participant flow
Recruitment details
A total of 104 participants (80 in Part 1 and 24 in Part 2) were randomized to receive either study medication or placebo. This study was conducted at a single center in Australia from 14-March-2016 to 16-June-2017.
Pre-assignment details
This study was planned to be conducted in 3 parts: Part 1 (single-day dosing) and Part 2 (repeat dose) dose-rising study in healthy participants and Part 3 (repeat dose) in obese participants. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
Participants by arm
| Arm | Count |
|---|---|
| Part 1- Placebo Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day. | 20 |
| Part 1-Cohort A1: GSK3008356 5 mg Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 1-Cohort A2: GSK3008356 10 mg Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 1-Cohort A3: GSK3008356 30 mg Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 30 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 1-Cohort A4: GSK3008356 75 mg Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 75 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 1-Cohort A5: GSK3008356 200 mg Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 200 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 1-Cohort A6: GSK3008356 125 mg Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 125 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 1-Cohort A7: GSK3008356 100 mg BID (0 h, 4 h) Eligible participants received GSK3008356 tablets via oral route (total dose of 200 mg such that one 100 mg dose was administered at 0 h and 4 h) along with a 30% fat by calorie meal approximately 2 hours after the morning dose in a single day. | 6 |
| Part 1-Cohort A8: GSK3008356 100 mg BID (0 h, 16 h) Eligible participants received GSK3008356 tablets via oral route (total dose of 200 mg such that one 100 mg dose was administered at 0 h and 16 h) along with a 30% fat by calorie meal approximately 2 hours after the morning dose in a single day. | 6 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose Participants in this arm were planned to receive a single evening dose of GSK3008356 tablets via oral route (total dose of 200 mg) along with a 30% fat by calorie meal approximately 2 hours after the evening dose; but this arm was cancelled. | 0 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses Eligible participants received GSK3008356 tablets via oral route (total dose of 90 mg such that a 10 mg dose was administered q1h for a total of 9 doses) along with a 30% fat by calorie meal approximately 2 hours after the first morning dose in a single day. | 6 |
| Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses Eligible participants received GSK3008356 tablets via oral route (total dose of 45 mg such that a 5 mg dose was administered q1h for a total of 9 doses) along with a 30% fat by calorie meal approximately 2 hours after the first morning dose in a single day. | 6 |
| Part 2-Placebo Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h) Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h) Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 2-Cohort B3: GSK3008356 3 mg BID (0 h, 16 h) Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 6 mg such that a 3 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose. | 6 |
| Part 3: Obese Participants Cohort 1 Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues. | 0 |
| Part 3: Obese Participants Cohort 2 Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues. | 0 |
| Part 3: Obese Participants Cohort 3 Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues. | 0 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 2 (Up to 22 Days) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 5 | 0 | 1 | 0 | 0 | 0 |
| Part 2 (Up to 22 Days) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1- Placebo | Part 1-Cohort A1: GSK3008356 5 mg | Part 1-Cohort A2: GSK3008356 10 mg | Part 1-Cohort A3: GSK3008356 30 mg | Part 1-Cohort A4: GSK3008356 75 mg | Part 1-Cohort A5: GSK3008356 200 mg | Part 1-Cohort A6: GSK3008356 125 mg | Part 1-Cohort A7: GSK3008356 100 mg BID (0 h, 4 h) | Part 1-Cohort A8: GSK3008356 100 mg BID (0 h, 16 h) | Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses | Part 2-Placebo | Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h) | Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h) | Part 2-Cohort B3: GSK3008356 3 mg BID (0 h, 16 h) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 24.8 Years STANDARD_DEVIATION 5.07 | 28.0 Years STANDARD_DEVIATION 16.49 | 25.8 Years STANDARD_DEVIATION 3.54 | 26.3 Years STANDARD_DEVIATION 4.46 | 26.0 Years STANDARD_DEVIATION 4.69 | 26.7 Years STANDARD_DEVIATION 5.65 | 24.3 Years STANDARD_DEVIATION 2.94 | 28.0 Years STANDARD_DEVIATION 7.04 | 31.5 Years STANDARD_DEVIATION 4.55 | 26.3 Years STANDARD_DEVIATION 4.76 | 24.7 Years STANDARD_DEVIATION 3.88 | 35.3 Years STANDARD_DEVIATION 12.75 | 26.5 Years STANDARD_DEVIATION 2.59 | 31.2 Years STANDARD_DEVIATION 11.51 | 25.8 Years STANDARD_DEVIATION 4.17 | 27.1 Years STANDARD_DEVIATION 7.18 |
| Race/Ethnicity, Customized Asian | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 12 Participants |
| Race/Ethnicity, Customized Brazilian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Chinese/Australian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Egyptian/New Zealand | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Half White Half Italian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Indian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Latin | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Middle Eastern | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Moroccan | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized South American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Spanish/Jamaican/English/Irish | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 15 Participants | 4 Participants | 4 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 4 Participants | 4 Participants | 3 Participants | 4 Participants | 6 Participants | 6 Participants | 5 Participants | 4 Participants | 79 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 20 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 0 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 20 | 1 / 6 | 0 / 6 | 1 / 6 | 1 / 6 | 3 / 6 | 3 / 6 | 3 / 6 | 3 / 6 | 0 / 0 | 0 / 6 | 3 / 6 | 2 / 6 | 5 / 6 | 3 / 6 | 3 / 6 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 20 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 0 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern
Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 1 are presented.
Time frame: Up to Day 4
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 4 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 3 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 3 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 2 Participants |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 3 Participants |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 2 Participants |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A8: GSK3008356 100 mg (0 h, 16 h) | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 3 Participants |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses | Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern | 0 Participants |
Primary
Part 1: Number of Participants With Abnormal Findings in Physical Examinations
A complete physical examination included assessment of the cardiovascular, respiratory, gastrointestinal, dermatologic and neurological systems, height, and weight. Height was measured and recorded only at screening. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight was recorded with the brief physical exam, but was not part of the brief physical exam. Number of participants with abnormal findings in physical examinations in Part 1 are presented.
Time frame: Up to Day 8
Population: Safety Population comprised of all participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 2 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 1 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 0 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 1 Participants |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 0 Participants |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 0 Participants |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 1 Participants |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 0 Participants |
| Part 1-Cohort A8: GSK3008356 100 mg (0 h, 16 h) | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 0 Participants |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 0 Participants |
| Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses | Part 1: Number of Participants With Abnormal Findings in Physical Examinations | 0 Participants |
Primary
Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or is associated with liver injury and impaired liver function.
Time frame: Up to Day 8
Population: Safety Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1- Placebo | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 5 Participants |
| Part 1- Placebo | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 2 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 1 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 1 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 3 Participants |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 4 Participants |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 4 Participants |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 3 Participants |
| Part 1-Cohort A8: GSK3008356 100 mg (0 h, 16 h) | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 3 Participants |
| Part 1-Cohort A8: GSK3008356 100 mg (0 h, 16 h) | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 0 Participants |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE | 4 Participants |
| Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses | Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | SAE | 0 Participants |
Primary
Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring
Continuous lead II cardiac telemetry or cardiac monitoring was performed on Day 1. Number of participants with clinically significant findings during cardiac monitoring in Part 1 are presented.
Time frame: Day 1
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 1 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A8: GSK3008356 100 mg (0 h, 16 h) | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses | Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
Primary
Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern
Hematology parameters included hematocrit, hemoglobin, platelets, white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cells (RBC) and reticulocytes. Clinical chemistry parameters included blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, uric acid, total protein, total and direct bilirubin, albumin, calcium, bile acids, chloride, creatinine, glucose (fasting/non-fasting), potassium, sodium and total carbon dioxide/bicarbonate. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine (WBC, RBC and casts) within 120 minutes of collection.
Time frame: Up to Day 8
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A8: GSK3008356 100 mg (0 h, 16 h) | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses | Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern | 1 Participants |
Primary
Part 1: Number of Participants With Vital Signs of Potential Clinical Concern
Vital signs included systolic and diastolic blood pressure and pulse rate and were measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring.
Time frame: Up to Day 8
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A8: GSK3008356 100 mg (0 h, 16 h) | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses | Part 1: Number of Participants With Vital Signs of Potential Clinical Concern | 1 Participants |
Primary
Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern
Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QTcF. Number of participants with 12-lead ECG values of potential clinical concern in Part 2 are presented.
Time frame: Up to Day 17
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern | 2 Participants |
Primary
Part 2: Number of Participants With Abnormal Findings in Physical Examination
A complete physical examination included assessment of the cardiovascular, respiratory, gastrointestinal, dermatologic and neurological systems, height, and weight. Height was measured and recorded only at screening. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight was recorded with the brief physical exam, but was not part of the brief physical exam. Number of participants with abnormal findings in physical examinations in Part 2 are presented.
Time frame: Up to Day 22
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 2: Number of Participants With Abnormal Findings in Physical Examination | 2 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Number of Participants With Abnormal Findings in Physical Examination | 2 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Number of Participants With Abnormal Findings in Physical Examination | 3 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 2: Number of Participants With Abnormal Findings in Physical Examination | 4 Participants |
Primary
Part 2: Number of Participants With AE and SAE
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or is associated with liver injury and impaired liver function.
Time frame: Up to Day 22
Population: Safety Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1- Placebo | Part 2: Number of Participants With AE and SAE | AE | 3 Participants |
| Part 1- Placebo | Part 2: Number of Participants With AE and SAE | SAE | 0 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Number of Participants With AE and SAE | SAE | 0 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Number of Participants With AE and SAE | AE | 5 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Number of Participants With AE and SAE | SAE | 0 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Number of Participants With AE and SAE | AE | 6 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 2: Number of Participants With AE and SAE | AE | 5 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 2: Number of Participants With AE and SAE | SAE | 0 Participants |
Primary
Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring
Continuous lead II cardiac telemetry or cardiac monitoring was performed on Day 1. Number of participants with clinically significant findings during cardiac monitoring in Part 2 are presented.
Time frame: Day 1 (Pre-dose to 4 hours post dose)
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring | 0 Participants |
Primary
Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern
Hematology parameters included hematocrit, hemoglobin, platelets, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cells and reticulocytes. Clinical chemistry parameters included blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, uric acid, total protein, total and direct bilirubin, albumin, calcium, bile acids, chloride, creatinine, glucose (fasting/non-fasting), potassium, sodium and total carbon dioxide/bicarbonate. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination (within 120 minutes of collection).
Time frame: Up to Day 22
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern | 0 Participants |
Primary
Part 2: Number of Participants With Vital Signs of Potential Clinical Concern
Vital signs included systolic and diastolic blood pressure and pulse and was measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring.
Time frame: Up to Day 22
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 2: Number of Participants With Vital Signs of Potential Clinical Concern | 1 Participants |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Number of Participants With Vital Signs of Potential Clinical Concern | 0 Participants |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 2: Number of Participants With Vital Signs of Potential Clinical Concern | 1 Participants |
Primary
Part 3: Number of Participants With 12-lead ECG Values of Potential Clinical Concern
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Up to Day 31
Population: Safety Population.
Primary
Part 3: Number of Participants With Abnormal Findings in Physical Examination
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Up to Day 36
Population: Safety Population.
Primary
Part 3: Number of Participants With AE and SAE
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Up to Day 36
Population: Safety Population.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Part 3: Number of Participants With AE and SAE | AE | — |
| Unknown | Part 3: Number of Participants With AE and SAE | SAE | — |
Primary
Part 3: Number of Participants With Clinically Significant Findings During Cardiac Monitoring
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Day 1 (Pre-dose to 4 hours post-dose)
Population: Safety Population.
Primary
Part 3: Number of Participants With Laboratory Values of Potential Clinical Concern
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Up to Day 36
Population: Safety Population.
Primary
Part 3: Number of Participants With Vital Signs of Potential Clinical Concern
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Up to Day 36
Population: Safety Population.
Secondary
Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24])
Blood samples for pharmacokinetic (PK) analysis of GSK3008356 were collected at the indicated time points.
Time frame: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose
Population: PK Parameter Population comprised of all participants in the PK Concentration Population (participants for whom a PK sample was obtained and analyzed) who received at least one active dose of GSK3008356 and provided PK parameters. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1- Placebo | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 184.934 Hours*nanograms/milliliters | Geometric Coefficient of Variation 21.32 |
| Part 1- Placebo | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 190.025 Hours*nanograms/milliliters | Geometric Coefficient of Variation 20.74 |
| Part 1- Placebo | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 190.004 Hours*nanograms/milliliters | Geometric Coefficient of Variation 20.74 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 307.945 Hours*nanograms/milliliters | Geometric Coefficient of Variation 17.76 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 313.349 Hours*nanograms/milliliters | Geometric Coefficient of Variation 18.23 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 313.369 Hours*nanograms/milliliters | Geometric Coefficient of Variation 18.23 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 840.806 Hours*nanograms/milliliters | Geometric Coefficient of Variation 27.54 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 840.740 Hours*nanograms/milliliters | Geometric Coefficient of Variation 27.54 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 834.100 Hours*nanograms/milliliters | Geometric Coefficient of Variation 27.52 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 1957.413 Hours*nanograms/milliliters | Geometric Coefficient of Variation 14.11 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 1951.059 Hours*nanograms/milliliters | Geometric Coefficient of Variation 14.25 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 1960.374 Hours*nanograms/milliliters | Geometric Coefficient of Variation 14.44 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 5481.127 Hours*nanograms/milliliters | Geometric Coefficient of Variation 17.64 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 5493.574 Hours*nanograms/milliliters | Geometric Coefficient of Variation 17.68 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 5454.538 Hours*nanograms/milliliters | Geometric Coefficient of Variation 17.24 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 4042.579 Hours*nanograms/milliliters | Geometric Coefficient of Variation 40.15 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 4035.511 Hours*nanograms/milliliters | Geometric Coefficient of Variation 40.12 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 4036.904 Hours*nanograms/milliliters | Geometric Coefficient of Variation 40.09 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 3364.475 Hours*nanograms/milliliters | Geometric Coefficient of Variation 271.56 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 3352.125 Hours*nanograms/milliliters | Geometric Coefficient of Variation 270.66 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 3336.805 Hours*nanograms/milliliters | Geometric Coefficient of Variation 277.78 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 5979.430 Hours*nanograms/milliliters | Geometric Coefficient of Variation 44.05 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 6018.925 Hours*nanograms/milliliters | Geometric Coefficient of Variation 44.4 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 5552.349 Hours*nanograms/milliliters | Geometric Coefficient of Variation 49.03 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 3121.146 Hours*nanograms/milliliters | Geometric Coefficient of Variation 14.38 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 3125.413 Hours*nanograms/milliliters | Geometric Coefficient of Variation 14.39 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 3121.146 Hours*nanograms/milliliters | Geometric Coefficient of Variation 14.38 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to inf) | 1181.752 Hours*nanograms/milliliters | Geometric Coefficient of Variation 62.07 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to 24) | 1179.327 Hours*nanograms/milliliters | Geometric Coefficient of Variation 61.84 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) | AUC (0 to t) | 1246.797 Hours*nanograms/milliliters | Geometric Coefficient of Variation 40.38 |
Secondary
Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356
Urine samples for PK analysis of GSK3008356 were collected at the indicated time points.
Time frame: Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours
Population: PK Parameter Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1- Placebo | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 7.958 Nanograms*10^5 | Standard Deviation 2.2225 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 8.699 Nanograms*10^5 | Standard Deviation 2.33 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 22.738 Nanograms*10^5 | Standard Deviation 8.364 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 62.332 Nanograms*10^5 | Standard Deviation 4.654 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 169.051 Nanograms*10^5 | Standard Deviation 20.0721 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 106.273 Nanograms*10^5 | Standard Deviation 50.783 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 170.777 Nanograms*10^5 | Standard Deviation 83.6483 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 143.269 Nanograms*10^5 | Standard Deviation 58.752 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 91.275 Nanograms*10^5 | Standard Deviation 17.8857 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 | 28.818 Nanograms*10^5 | Standard Deviation 11.7506 |
Secondary
Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC
Dose proportionality was assessed from the AUC (0 to t) and AUC (0 to inf) obtained from multiple cohorts in Part 1. The dose proportionality was assessed using a power model on logarithmic transformation of AUC with the logarithmic transformation of dose as the single covariate in the linear regression. Point estimates and 90% confidence interval are presented.
Time frame: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose
Population: PK Parameter Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1- Placebo | Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC | AUC (0 to t): Cohort A5 vs. Cohort A1 | 0.92 Slope of log dose |
| Part 1- Placebo | Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC | AUC (0 to t): Cohort A7 vs. Cohort A1 | 0.78 Slope of log dose |
| Part 1- Placebo | Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC | AUC (0 to t): Cohort A8 vs. Cohort A1 | 0.94 Slope of log dose |
| Part 1- Placebo | Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC | AUC (0 to inf): Cohort A5 vs. Cohort A1 | 0.91 Slope of log dose |
| Part 1- Placebo | Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC | AUC (0 to inf): Cohort A7 vs. Cohort A1 | 0.78 Slope of log dose |
| Part 1- Placebo | Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC | AUC (0 to inf): Cohort A8 vs. Cohort A1 | 0.94 Slope of log dose |
Secondary
Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg vs. 200 mg After Single Dose Administration Based on Cmax
Dose proportionality was assessed from the Cmax obtained from multiple cohorts in Part 1. The dose proportionality was assessed using a power model on logarithmic transformation of Cmax, with the logarithmic transformation of dose as the single covariate in the linear regression. For Cmax, only a single dose group from Cohort 1 to Cohort 6 was considered since other cohorts are multiple dosing where Cmax is so different from that of single dose group. Data for Cohort A5 vs. Cohort A1 is presented, Point estimates and 90% confidence interval are presented.
Time frame: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose
Population: PK Parameter Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1- Placebo | Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg vs. 200 mg After Single Dose Administration Based on Cmax | 0.81 Slope of log dose |
Secondary
Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356
Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.
Time frame: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post dose on Day 1 and 36, 48, and 72 hours post-dose
Population: PK Parameter Population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1- Placebo | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 92.417 Nanograms per milliliters | Geometric Coefficient of Variation 45.4 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 190.655 Nanograms per milliliters | Geometric Coefficient of Variation 22.4 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 458.496 Nanograms per milliliters | Geometric Coefficient of Variation 33.1 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 890.913 Nanograms per milliliters | Geometric Coefficient of Variation 15.87 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 1865.337 Nanograms per milliliters | Geometric Coefficient of Variation 44.38 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 1568.035 Nanograms per milliliters | Geometric Coefficient of Variation 27.58 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 793.544 Nanograms per milliliters | Geometric Coefficient of Variation 260.32 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 946.060 Nanograms per milliliters | Geometric Coefficient of Variation 84.09 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 444.545 Nanograms per milliliters | Geometric Coefficient of Variation 19.61 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 | 202.817 Nanograms per milliliters | Geometric Coefficient of Variation 9.81 |
Secondary
Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356
Preliminary pharmacodynamics of GSK3008356 was evaluated by assessing the postprandial triglyceride levels at the indicated time points. Corrected triglyceride value (Day 1) at each nominal sampling time point was defined as the corresponding post dose value by adding the following value: Part 1 Day 1 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 1 (1 hour + 2 hour)/2). Mean triglyceride levels are presented.
Time frame: Day 1 at 1,2,3,4,5,6,7,8,9,12 hours post-dose
Population: Pharmacodynamic (PD) Population comprised of participants in the Safety population for whom at least one postprandial triglyceride sample was obtained and analyzed at Baseline and post Baseline. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.725 Millimoles/Liters | Standard Deviation 0.2697 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.825 Millimoles/Liters | Standard Deviation 0.2505 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 1.425 Millimoles/Liters | Standard Deviation 0.4612 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.825 Millimoles/Liters | Standard Deviation 0.2545 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 1.275 Millimoles/Liters | Standard Deviation 0.4783 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 1.058 Millimoles/Liters | Standard Deviation 0.3056 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 0.925 Millimoles/Liters | Standard Deviation 0.2505 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 1.158 Millimoles/Liters | Standard Deviation 0.4018 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 1.308 Millimoles/Liters | Standard Deviation 0.4092 |
| Part 1- Placebo | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 1.008 Millimoles/Liters | Standard Deviation 0.4042 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 0.967 Millimoles/Liters | Standard Deviation 0.3601 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 0.833 Millimoles/Liters | Standard Deviation 0.3093 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 0.900 Millimoles/Liters | Standard Deviation 0.3178 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 0.867 Millimoles/Liters | Standard Deviation 0.2714 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 0.750 Millimoles/Liters | Standard Deviation 0.2683 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.733 Millimoles/Liters | Standard Deviation 0.2273 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.783 Millimoles/Liters | Standard Deviation 0.2733 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.817 Millimoles/Liters | Standard Deviation 0.2338 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 0.983 Millimoles/Liters | Standard Deviation 0.3531 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.583 Millimoles/Liters | Standard Deviation 0.1693 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.700 Millimoles/Liters | Standard Deviation 0.2168 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 0.950 Millimoles/Liters | Standard Deviation 0.3493 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.700 Millimoles/Liters | Standard Deviation 0.3178 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.717 Millimoles/Liters | Standard Deviation 0.2503 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.783 Millimoles/Liters | Standard Deviation 0.2805 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 0.733 Millimoles/Liters | Standard Deviation 0.3573 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 0.950 Millimoles/Liters | Standard Deviation 0.2864 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 1.017 Millimoles/Liters | Standard Deviation 0.3502 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 0.800 Millimoles/Liters | Standard Deviation 0.2168 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 0.850 Millimoles/Liters | Standard Deviation 0.3464 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 0.850 Millimoles/Liters | Standard Deviation 0.2608 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 0.767 Millimoles/Liters | Standard Deviation 0.1722 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 0.850 Millimoles/Liters | Standard Deviation 0.2 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.617 Millimoles/Liters | Standard Deviation 0.2696 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.650 Millimoles/Liters | Standard Deviation 0.3317 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 0.767 Millimoles/Liters | Standard Deviation 0.3281 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 0.767 Millimoles/Liters | Standard Deviation 0.3817 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.667 Millimoles/Liters | Standard Deviation 0.2893 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.667 Millimoles/Liters | Standard Deviation 0.209 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 0.817 Millimoles/Liters | Standard Deviation 0.2582 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 0.675 Millimoles/Liters | Standard Deviation 0.3947 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 0.625 Millimoles/Liters | Standard Deviation 0.3126 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.508 Millimoles/Liters | Standard Deviation 0.2538 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.775 Millimoles/Liters | Standard Deviation 0.4263 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 0.558 Millimoles/Liters | Standard Deviation 0.3007 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 0.742 Millimoles/Liters | Standard Deviation 0.4176 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 0.658 Millimoles/Liters | Standard Deviation 0.3639 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 0.692 Millimoles/Liters | Standard Deviation 0.4104 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.592 Millimoles/Liters | Standard Deviation 0.2691 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.675 Millimoles/Liters | Standard Deviation 0.3283 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 1.008 Millimoles/Liters | Standard Deviation 0.347 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 0.842 Millimoles/Liters | Standard Deviation 0.2289 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.925 Millimoles/Liters | Standard Deviation 0.2525 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.875 Millimoles/Liters | Standard Deviation 0.3029 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 0.842 Millimoles/Liters | Standard Deviation 0.2836 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.792 Millimoles/Liters | Standard Deviation 0.2333 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 0.858 Millimoles/Liters | Standard Deviation 0.2905 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 0.825 Millimoles/Liters | Standard Deviation 0.1994 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 0.925 Millimoles/Liters | Standard Deviation 0.2444 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.842 Millimoles/Liters | Standard Deviation 0.32 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.783 Millimoles/Liters | Standard Deviation 0.291 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 0.717 Millimoles/Liters | Standard Deviation 0.216 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.633 Millimoles/Liters | Standard Deviation 0.1992 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.750 Millimoles/Liters | Standard Deviation 0.2145 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 1.000 Millimoles/Liters | Standard Deviation 0.532 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 1.017 Millimoles/Liters | Standard Deviation 0.5663 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 0.917 Millimoles/Liters | Standard Deviation 0.5663 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 0.883 Millimoles/Liters | Standard Deviation 0.4782 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 0.850 Millimoles/Liters | Standard Deviation 0.445 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.883 Millimoles/Liters | Standard Deviation 0.3173 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 1.025 Millimoles/Liters | Standard Deviation 0.3984 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 1.008 Millimoles/Liters | Standard Deviation 0.4913 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 1.258 Millimoles/Liters | Standard Deviation 0.6078 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 1.242 Millimoles/Liters | Standard Deviation 0.4375 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 1.175 Millimoles/Liters | Standard Deviation 0.5681 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 1.075 Millimoles/Liters | Standard Deviation 0.5223 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.875 Millimoles/Liters | Standard Deviation 0.4084 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 1.042 Millimoles/Liters | Standard Deviation 0.4954 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 1.292 Millimoles/Liters | Standard Deviation 0.4893 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 0.958 Millimoles/Liters | Standard Deviation 0.4188 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 0.700 Millimoles/Liters | Standard Deviation 0.1949 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.667 Millimoles/Liters | Standard Deviation 0.1966 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.600 Millimoles/Liters | Standard Deviation 0.2 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.700 Millimoles/Liters | Standard Deviation 0.2236 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 0.750 Millimoles/Liters | Standard Deviation 0.2588 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 0.617 Millimoles/Liters | Standard Deviation 0.178 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 0.670 Millimoles/Liters | Standard Deviation 0.2197 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.667 Millimoles/Liters | Standard Deviation 0.2066 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 0.700 Millimoles/Liters | Standard Deviation 0.2098 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 0.617 Millimoles/Liters | Standard Deviation 0.2714 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 7 hour post-dose | 0.608 Millimoles/Liters | Standard Deviation 0.2923 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 5 hour post-dose | 0.608 Millimoles/Liters | Standard Deviation 0.3024 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 8 hour post-dose | 0.592 Millimoles/Liters | Standard Deviation 0.3541 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 4 hour post-dose | 0.592 Millimoles/Liters | Standard Deviation 0.2635 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 3 hour post-dose | 0.675 Millimoles/Liters | Standard Deviation 0.2162 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 9 hour post-dose | 0.658 Millimoles/Liters | Standard Deviation 0.3484 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 2 hour post-dose | 0.692 Millimoles/Liters | Standard Deviation 0.1985 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 1 hour post-dose | 0.775 Millimoles/Liters | Standard Deviation 0.2842 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 12 hour post-dose | 0.792 Millimoles/Liters | Standard Deviation 0.3247 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 | Day 1, 6 hour post-dose | 0.642 Millimoles/Liters | Standard Deviation 0.3427 |
Secondary
Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356
Urine samples for PK analysis of GSK3008356 were collected at the indicated time points.
Time frame: Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours
Population: PK Parameter Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1- Placebo | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 4115.667 Milliliters per hour | Standard Deviation 855.3612 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 2752.580 Milliliters per hour | Standard Deviation 595.2028 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 2659.878 Milliliters per hour | Standard Deviation 645.2413 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 3214.711 Milliliters per hour | Standard Deviation 539.48 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 3091.822 Milliliters per hour | Standard Deviation 494.6096 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 2751.679 Milliliters per hour | Standard Deviation 1582.5976 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 3343.542 Milliliters per hour | Standard Deviation 765.2069 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 2638.871 Milliliters per hour | Standard Deviation 2108.5407 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 2935.504 Milliliters per hour | Standard Deviation 632.6009 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 | 1697.050 Milliliters per hour | Standard Deviation 800.8092 |
Secondary
Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356
Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.
Time frame: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post dose on Day 1 and 36, 48, and 72 hours post-dose
Population: PK Parameter Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1- Placebo | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 1.501 Hours | Standard Deviation 0.2048 |
| Part 1- Placebo | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 0.833 Hours | Standard Deviation 0.4082 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 1.425 Hours | Standard Deviation 0.1885 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 0.542 Hours | Standard Deviation 0.2458 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 1.623 Hours | Standard Deviation 0.1928 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 0.750 Hours | Standard Deviation 0.2739 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 2.113 Hours | Standard Deviation 1.2949 |
| Part 1-Cohort A3: GSK3008356 30 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 0.756 Hours | Standard Deviation 0.2681 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 0.917 Hours | Standard Deviation 0.5845 |
| Part 1-Cohort A4: GSK3008356 75 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 4.545 Hours | Standard Deviation 3.2092 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 0.917 Hours | Standard Deviation 0.5845 |
| Part 1-Cohort A5: GSK3008356 200 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 2.779 Hours | Standard Deviation 0.7223 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 1.667 Hours | Standard Deviation 2.137 |
| Part 1-Cohort A6: GSK3008356 125 mg | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 2.540 Hours | Standard Deviation 0.6481 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 3.922 Hours | Standard Deviation 6.9303 |
| Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h) | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 1.752 Hours | Standard Deviation 0.247 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 6.225 Hours | Standard Deviation 3.0329 |
| Part 1-Cohort A9: GSK3008356 200 mg Evening Dose | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 1.992 Hours | Standard Deviation 0.205 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | t1/2 | 1.941 Hours | Standard Deviation 0.4058 |
| Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses | Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 | Tmax | 6.169 Hours | Standard Deviation 2.3376 |
Secondary
Part 2: Ae of GSK3008356 on Day 14
Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study.
Time frame: Pre-dose and 24 hours post-dose on Day 14
Population: PK Parameter Population.
Secondary
Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14
Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose.
Time frame: Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Population: PK Parameter Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1- Placebo | Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14 | AUC (0 to tau) on Day 1 | 279.222 Hours*nanograms/milliliters | Geometric Coefficient of Variation 26.39 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14 | AUC (0 to tau) on Day 1 | 31.959 Hours*nanograms/milliliters | Geometric Coefficient of Variation 25.16 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14 | AUC (0 to tau) on Day 14 | 37.429 Hours*nanograms/milliliters | Geometric Coefficient of Variation 21.97 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14 | AUC (0 to tau) on Day 1 | 107.191 Hours*nanograms/milliliters | Geometric Coefficient of Variation 32.12 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14 | AUC (0 to tau) on Day 14 | 101.151 Hours*nanograms/milliliters | Geometric Coefficient of Variation 20.2 |
Secondary
Part 2: CLr of GSK3008356 on Day 14
Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study.
Time frame: Pre-dose and 24 hours post-dose on Day 14
Population: PK Parameter Population.
Secondary
Part 2: Cmax of GSK3008356 on Day 1 and Day 14
Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose.
Time frame: Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Population: PK Parameter Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1- Placebo | Part 2: Cmax of GSK3008356 on Day 1 and Day 14 | Day 1 | 187.032 Nanograms/milliliters | Geometric Coefficient of Variation 28.69 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Cmax of GSK3008356 on Day 1 and Day 14 | Day 14 | 16.424 Nanograms/milliliters | Geometric Coefficient of Variation 33.86 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Cmax of GSK3008356 on Day 1 and Day 14 | Day 1 | 17.638 Nanograms/milliliters | Geometric Coefficient of Variation 40.02 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Cmax of GSK3008356 on Day 1 and Day 14 | Day 1 | 77.326 Nanograms/milliliters | Geometric Coefficient of Variation 31.73 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Cmax of GSK3008356 on Day 1 and Day 14 | Day 14 | 46.736 Nanograms/milliliters | Geometric Coefficient of Variation 17.52 |
Secondary
Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC
Dose proportionality was assessed from Day 1 and Day 14 AUC (0 to tau) obtained from multiple cohorts in Part 2. The dose proportionality was assessed using a power model on logarithmic transformation of AUC, with the logarithmic transformation of dose as the single covariate in the linear regression. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. Point estimates and 90% confidence interval are presented.
Time frame: Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Population: PK Parameter Population. Only those parameters available at the specified time points were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1- Placebo | Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC | AUC (0 to tau); Cohort B1 vs. Cohort B2 on Day 1 | 0.94 Slope of log dose |
| Part 1- Placebo | Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC | AUC (0 to tau); Cohort B3 vs. Cohort B2 on Day 1 | 1.10 Slope of log dose |
| Part 1- Placebo | Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC | AUC (0 to tau); Cohort B3 vs. Cohort B2 on Day 14 | 0.90 Slope of log dose |
| Part 1- Placebo | Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC | AUC (0 to inf); Cohort B1 vs. Cohort B2 on Day 1 | 0.94 Slope of log dose |
| Part 1- Placebo | Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC | AUC (0 to inf); Cohort B3 vs. Cohort B2 on Day 1 | 1.10 Slope of log dose |
Secondary
Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on Cmax
The dose proportionality was assessed using a power model on logarithmic transformation of Cmax, with the logarithmic transformation of dose as the single covariate in the linear regression. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. Point estimates and 90% confidence interval are presented for Day 1 and Day 14 of Part 2.
Time frame: Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post-dose
Population: PK Parameter Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1- Placebo | Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on Cmax | Cmax; Cohort B1 vs. Cohort B2 on Day 1 | 1.03 Slope of log dose |
| Part 1- Placebo | Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on Cmax | Cmax; Cohort B3 vs. Cohort B2 on Day 1 | 1.35 Slope of log dose |
| Part 1- Placebo | Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on Cmax | Cmax; Cohort B3 vs. Cohort B2 on Day 14 | 0.95 Slope of log dose |
Secondary
Part 2: Observed Accumulation Ratio of GSK3008356
Observed accumulation ratio based on AUC(0- tau) is (Ro), and based on Cmax is (RCmax). Ro was calculated as the ratio \[AUC0-tau on the final day (Day 14)\]/\[ AUC0-tau on Day 1\] and Rcmax was calculated as the ratio \[Cmax on the final day (Day 14)\]/\[Cmax on Day 1\]. Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.
Time frame: Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Population: PK Parameter Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Observed Accumulation Ratio of GSK3008356 | Ro | 1.171 Ratio | Geometric Coefficient of Variation 13.52 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Observed Accumulation Ratio of GSK3008356 | Rcmax | 0.931 Ratio | Geometric Coefficient of Variation 22.64 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Observed Accumulation Ratio of GSK3008356 | Ro | 1.010 Ratio | Geometric Coefficient of Variation 19.76 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Observed Accumulation Ratio of GSK3008356 | Rcmax | 0.606 Ratio | Geometric Coefficient of Variation 38.82 |
Secondary
Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356
Preliminary pharmacodynamics of GSK3008356 was evaluated by assessing the postprandial triglyceride levels at the indicated time points. Corrected TG value (Day 1 and Day 14) at each nominal sampling time point defined as the corresponding post dose value by adding the following value: Part 2 Day 1 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 1 (1 hour + 2 hour)/2); Part 2 Day 14 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 14 (1 hour + 2 hour)/2). Mean triglyceride levels are presented.
Time frame: Day 1 (1, 2, 3, 4, 5, 6, 7, 8, 9 and 12 hours post-dose) and Day 14 (1, 2, 3, 4, 5, 6, 7, 8, 9 and 12 hours post-dose)
Population: PD Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 3 hour post-dose | 0.767 Millimoles/Liter | Standard Deviation 0.4987 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 12 hour post-dose | 0.800 Millimoles/Liter | Standard Deviation 0.4359 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 8 hour post-dose | 1.283 Millimoles/Liter | Standard Deviation 0.7561 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 4 hour post-dose | 0.883 Millimoles/Liter | Standard Deviation 0.4956 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 2 hour post-dose | 0.800 Millimoles/Liter | Standard Deviation 0.4219 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 7 hour post-dose | 1.300 Millimoles/Liter | Standard Deviation 0.5933 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 5 hour post-dose | 1.033 Millimoles/Liter | Standard Deviation 0.4633 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 1 hour post-dose | 0.867 Millimoles/Liter | Standard Deviation 0.4987 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 6 hour post-dose | 1.150 Millimoles/Liter | Standard Deviation 0.499 |
| Part 1- Placebo | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 9 hour post-dose | 1.050 Millimoles/Liter | Standard Deviation 0.6442 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 4 hour post-dose | 1.017 Millimoles/Liter | Standard Deviation 0.284 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 2 hour post-dose | 0.817 Millimoles/Liter | Standard Deviation 0.2582 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 3 hour post-dose | 0.950 Millimoles/Liter | Standard Deviation 0.2757 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 12 hour post-dose | 0.800 Millimoles/Liter | Standard Deviation 0.4889 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 1 hour post-dose | 0.950 Millimoles/Liter | Standard Deviation 0.3017 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 2 hour post-dose | 0.783 Millimoles/Liter | Standard Deviation 0.2317 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 3 hour post-dose | 0.883 Millimoles/Liter | Standard Deviation 0.3189 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 4 hour post-dose | 0.833 Millimoles/Liter | Standard Deviation 0.3235 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 5 hour post-dose | 1.017 Millimoles/Liter | Standard Deviation 0.4309 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 6 hour post-dose | 1.050 Millimoles/Liter | Standard Deviation 0.6189 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 7 hour post-dose | 1.233 Millimoles/Liter | Standard Deviation 0.7005 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 8 hour post-dose | 1.167 Millimoles/Liter | Standard Deviation 0.6578 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 9 hour post-dose | 1.000 Millimoles/Liter | Standard Deviation 0.6293 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 12 hour post-dose | 0.717 Millimoles/Liter | Standard Deviation 0.3996 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 1 hour post-dose | 0.917 Millimoles/Liter | Standard Deviation 0.3077 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 5 hour post-dose | 1.100 Millimoles/Liter | Standard Deviation 0.386 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 6 hour post-dose | 1.217 Millimoles/Liter | Standard Deviation 0.5066 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 7 hour post-dose | 1.367 Millimoles/Liter | Standard Deviation 0.5345 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 8 hour post-dose | 1.367 Millimoles/Liter | Standard Deviation 0.4834 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 9 hour post-dose | 0.817 Millimoles/Liter | Standard Deviation 0.4844 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 1 hour post-dose | 1.217 Millimoles/Liter | Standard Deviation 0.3697 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 12 hour post-dose | 0.720 Millimoles/Liter | Standard Deviation 0.6079 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 12 hour post-dose | 1.033 Millimoles/Liter | Standard Deviation 0.2041 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 7 hour post-dose | 1.460 Millimoles/Liter | Standard Deviation 0.2608 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 1 hour post-dose | 1.020 Millimoles/Liter | Standard Deviation 0.249 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 2 hour post-dose | 0.960 Millimoles/Liter | Standard Deviation 0.1597 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 3 hour post-dose | 1.080 Millimoles/Liter | Standard Deviation 0.1924 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 9 hour post-dose | 1.467 Millimoles/Liter | Standard Deviation 0.5037 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 4 hour post-dose | 1.020 Millimoles/Liter | Standard Deviation 0.2907 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 5 hour post-dose | 1.317 Millimoles/Liter | Standard Deviation 0.4655 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 9 hour post-dose | 1.220 Millimoles/Liter | Standard Deviation 0.5239 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 6 hour post-dose | 1.500 Millimoles/Liter | Standard Deviation 0.5523 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 4 hour post-dose | 1.067 Millimoles/Liter | Standard Deviation 0.322 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 5 hour post-dose | 1.060 Millimoles/Liter | Standard Deviation 0.2748 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 7 hour post-dose | 1.700 Millimoles/Liter | Standard Deviation 0.3987 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 3 hour post-dose | 0.983 Millimoles/Liter | Standard Deviation 0.2503 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 8 hour post-dose | 1.380 Millimoles/Liter | Standard Deviation 0.4764 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 8 hour post-dose | 1.717 Millimoles/Liter | Standard Deviation 0.4676 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 1, 2 hour post-dose | 0.950 Millimoles/Liter | Standard Deviation 0.2236 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 | Day 14, 6 hour post-dose | 1.260 Millimoles/Liter | Standard Deviation 0.3943 |
Secondary
Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14
Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose.
Time frame: Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Population: PK Parameter Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1- Placebo | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | t1/2 on Day 1 | 1.319 Hours | Standard Deviation 0.1512 |
| Part 1- Placebo | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | Tmax on Day 1 | 0.517 Hours | Standard Deviation 0.0279 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | t1/2 on Day 1 | 1.312 Hours | Standard Deviation 0.1369 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | t1/2 on Day 14 | 1.406 Hours | Standard Deviation 0.2138 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | Tmax on Day 1 | 0.583 Hours | Standard Deviation 0.2041 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | Tmax on Day 14 | 0.875 Hours | Standard Deviation 0.6275 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | t1/2 on Day 1 | 1.443 Hours | Standard Deviation 0.1624 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | Tmax on Day 1 | 0.436 Hours | Standard Deviation 0.1511 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | t1/2 on Day 14 | 2.115 Hours | Standard Deviation 1.3252 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 | Tmax on Day 14 | 0.550 Hours | Standard Deviation 0.2739 |
Secondary
Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing
Ctrough is the observed concentration at the end of a dosing interval, immediately before next administration. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose.
Time frame: Pre-dose on Days 2, 4, 5, 6, 12, 13, 14 and the 24 hours post-dose on Day 14
Population: PK Parameter Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1- Placebo | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 1, 24 Hour | 11.953 Nanograms/Milliliters | Standard Deviation 7.8239 |
| Part 1- Placebo | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 6, Pre-Dose | 2.880 Nanograms/Milliliters | Standard Deviation 2.6985 |
| Part 1- Placebo | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 5, Pre-Dose | 4.790 Nanograms/Milliliters | Standard Deviation 2.2425 |
| Part 1- Placebo | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 4, Pre-Dose | 11.528 Nanograms/Milliliters | Standard Deviation 7.2515 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 6, Pre-Dose | 0.475 Nanograms/Milliliters | Standard Deviation 0.7364 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 1, 24 Hour | 2.595 Nanograms/Milliliters | Standard Deviation 2.0718 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 4, Pre-Dose | 1.362 Nanograms/Milliliters | Standard Deviation 0.7706 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 5, Pre-Dose | 1.392 Nanograms/Milliliters | Standard Deviation 1.6697 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 12, Pre-Dose | 0.205 Nanograms/Milliliters | Standard Deviation 0.5021 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 13, Pre-Dose | 0.325 Nanograms/Milliliters | Standard Deviation 0.7961 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 14, Pre-Dose | 1.587 Nanograms/Milliliters | Standard Deviation 1.3835 |
| Part 1-Cohort A1: GSK3008356 5 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 14, 24 Hour | 1.420 Nanograms/Milliliters | Standard Deviation 0.6255 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 14, 24 Hour | 1.866 Nanograms/Milliliters | Standard Deviation 0.4191 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 12, Pre-Dose | 1.934 Nanograms/Milliliters | Standard Deviation 1.0154 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 14, Pre-Dose | 4.368 Nanograms/Milliliters | Standard Deviation 3.3806 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 13, Pre-Dose | 3.756 Nanograms/Milliliters | Standard Deviation 2.1434 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 5, Pre-Dose | 6.595 Nanograms/Milliliters | Standard Deviation 4.8009 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 4, Pre-Dose | 1.940 Nanograms/Milliliters | Standard Deviation 2.2364 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 1, 24 Hour | 4.025 Nanograms/Milliliters | Standard Deviation 1.7353 |
| Part 1-Cohort A2: GSK3008356 10 mg | Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing | Day 6, Pre-Dose | 3.206 Nanograms/Milliliters | Standard Deviation 1.9157 |
Secondary
Part 3: Ae of GSK3008356 on Day 28
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Day 28 in each cohort
Population: PK Parameter Population.
Secondary
Part 3: AUC (0-tau) of GSK3008356 on Day 1 and Day 28
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Population: PK Parameter Population.
Secondary
Part 3: CLr of GSK3008356 on Day 28
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Day 28 in each cohort
Population: PK Parameter Population.
Secondary
Part 3: Cmax of GSK3008356 on Day 1 and Day 28
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Population: PK Parameter Population.
Secondary
Part 3: Ctrough to Assess Steady State of GSK3008356 Following 28-day Repeat Dosing
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Population: PK Parameter Population.
Secondary
Part 3: Dose Proportionality of GSK3008356
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Population: PK Parameter Population.
Secondary
Part 3: Observed Accumulation Ratio of GSK3008356
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Population: PK Parameter Population.
Secondary
Part 3: Postprandial Triglyceride Levels Following 28-day Repeat Dosing of GSK3008356 in Obese Participants
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Day -1, Day 1, and Day 28 in cohort 1, and Day 1, Day 2, and Day 28 in cohorts 2 and 3
Population: PD Population.
Secondary
Part 3: t1/2 of GSK3008356 on Day 28
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, 24, 36, 48, and 72 hours post-dose on Day 28
Population: PK Parameter Population.
Secondary
Part 3: Tmax of GSK3008356 on Day 1 and Day 28
Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Population: PK Parameter Population.