Systemic Lupus Erythematosus
Conditions
Keywords
Pharmacokinetics, GSK2586184, Simvastatin, Rosuvastatin, Poloxamer
Brief summary
This study is a Phase I, two-part, open-label study designed to evaluate the effect of repeated doses of GSK2586184 on the pharmacokinetics (PK) of Simvastatin and Rosuvastatin in healthy volunteers (Cohort A), and to evaluate the pharmacokinetics of a new tablet formulation of GSK2586184 in healthy male volunteers (Cohort B). Cohort A is a single sequence drug interaction study in which 28 subjects (14 female and 14 male subjects) will be enrolled. Each subject will receive single doses of Simvastatin and Rosuvastatin on two occasions, once alone and once following administration of repeated doses of GSK2586184. Cohort B is a 3-way crossover PK study in which 9 male subjects will be randomized (3 subjects to each treatment sequence). Each subject will receive a single dose of the standard formulation of GSK2586184 with food and two doses of a new formulation of GSK2586184, once with food and once in a fasted state, according to their treatment sequence, with a 3-day wash out between doses. The primary aim of the study is to investigate the effects of GSK2586184 on the pharmacokinetics of the 2 statins and to assess the impact of dosing with and without food on a new formulation of GSK2586184 tablet.
Interventions
DRUGGSK2586184 standard formulation
GSK2586184 standard formulation is a white film coated round biconvex 200 mg oral tablet. For cohort A, it is to be administered at 400 mg (200 mg x 2 tablets) twice daily from Day 6 to Day 14. For cohort B, it is to be administered at 400 mg (200 mg x 2 tablets) single dose after standard breakfast either on Day 1, 4 and 7 according to the treatment sequence, each separated by a 3-day wash out period.
DRUGSimvastatin
Simvastatin 10 mg oral tablet is peach-coloured, oval-shaped tablets. It is to be administered orally as a single dose of 10 mg tablet on the mornings of Day 1 and Day 10.
DRUGRosuvastatin
GSK2586184 new formulation without poloxamer is a white film coated round biconvex 200 mg oral tablet. In cohort B, it is to be administered at 400 mg (200 mg x 2 tablets) single dose once after standard breakfast and once after overnight fasting, either on Day 1, 4 and 7 according to the treatment sequence, each separated by a 3-day washout period.
DRUGGSK2586184 new formulation
GSK2586184 new formulation without poloxamer is a white film coated round biconvex 200 mg oral tablet. In cohort B, it is to be administered at 400 mg (200 mg x 2 tablets) single dose once after standard breakfast and once after overnight fasting, either on Day 1, 4 and 7 according to the treatment sequence, each separated by a 3-day washout period.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Males and females aged between 18 and 65 years of age inclusive, at the time of signing the informed consent. (Females are only eligible for Cohort A). * Healthy as determined by a responsible and experienced physician, 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 GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Subjects with Hemoglobin (Hgb), Hematocrit (HCT), White blood cells (WBC), neutrophil or platelet values outside the normal range should always be excluded from enrolment. * Body Mass Index (BMI) within the range 18 - 30 Kilogram per meter square (kg/m\^2) (inclusive). * For Cohort A only, a female subject is eligible to participate if she is of non-childbearing potential, defined as: Pre-menopausal females with a documented tubal ligation, tubal occlusion procedure followed by a hysterosalpingogram that confirmed bilateral tubal occlusion, bilateral salpingectomy or hysterectomy \[ documented refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli-international units per milliliter mIU/mL and estradiol \< 40 picogram/milliliter (pg/mL) (\<147 picomole/liter is confirmatory\]. * Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods: Condom plus partner use of a highly effective contraceptive or abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. This criterion must be followed from the time of the first dose of study medication and for at least 2 weeks after their last dose. * Normal creatinine clearance values at screening (calculated from serum creatinine by a predicting equation using Cockcroft-Gault formula), normal serum creatinine value as defined by the local reference laboratory, normal urine microscopy and no significant proteinuria on dipstick testing. * Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<= 1.5 x Upper Limit of Normal \[ULN\] (isolated bilirubin \>1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \< 35 %). * Based on averaged QT duration corrected for heart rate by Fridericia's formula (QTcF) values of triplicate ECGs obtained over a brief recording period: QTcF \< 450 millisecond (msec); or QTcF \< 480 msec in subjects with Bundle Branch Block. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A: AUC (zero to infinity), AUC (0-t) and Cmax of Rosuvastatin alone and in the presence of GSK2586184 | Days 3 and 12 (1 hour (h) pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 and 72 hours (hrs) post-dose) | Blood samples will be collected to analyse PK parameters of Rosuvastatin including area under the plasma concentration-time curve from time zero to infinity \[AUC(0-inf)\], area under the plasma concentration-time curve from time zero to the last quantifiable concentration \[AUC(0-t)\] and the maximum observed plasma concentration (Cmax). |
| Cohort A: AUC (zero to infinity), AUC(0-t) and Cmax of Simvastatin/Simvastatin acid alone and in the presence of GSK2586184. | Days 1 and 10 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24 and 48 hrs post-dose) | Blood samples will be collected to analyse PK parameters of Simvastatin including AUC(0-inf), AUC(0-t) and Cmax. |
| Cohort B: AUC (zero to infinity), AUC(0-24), Tmax and Cmax of GSK2586184 (standard formulation, containing poloxamer) and GSK2586184 (new formulation, without-poloxamer). | Day 1, 4 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hrs post dose) and Day 7 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24) | Blood samples will be collected to analyse PK parameters of GSK2586184 (standard and new formulation) including AUC(0-inf), area under the plasma concentration-time curve from time 0 to 24 hrs (AUC(0-24)), time to maximum observed plasma drug concentration (Tmax) and Cmax. |
| Cohort B: AUC(zero to infinity), AUC(0-24), Tmax and Cmax of GSK2586184 (new formulation, without-poloxamer) dosed with and without food. | Day 1, 4 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hrs post dose) and Day 7 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24) | Blood samples will be collected to analyse PK parameters of GSK2586184 (new formulation, without-poloxamer) including AUC (0-inf), AUC(0-24), Tmax and Cmax. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A: AUC (0-12) and Cmax of two metabolites of GSK2586184 (GSK2983628 and GSK3100466) at steady state | Day 9 (1 h pre-dose, and 0.5, 1, 2, 4, 6, 8, 10 and 12 hrs post dose) | Blood samples will be collected to analyse PK parameters of GSK2983628 and GSK3100466 at steady state including AUC (0-12) and Cmax. |
| Cohort B: AUC (zero to infinity), AUC(0-24), Cmax, Tmax and t1/2 of two metabolites of GSK2586184 (GSK2983628 and GSK3100466) | Day 1, 4 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hrs post dose) and Day 7 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24) | Blood samples will be collected to analyse PK parameters of GSK2983628 and GSK3100466 including AUC (0-inf), AUC (0-24), Cmax, Tmax and terminal phase half-life (t1/2). |
| Cohort A: AUC(0-12) and Cmax of GSK2586184 at steady state | Day 9 (1 h pre-dose, and 0.5, 1, 2, 4, 6, 8, 10 and 12 hrs post dose) | Blood samples will be collected to analyse PK parameters of GSK2586184 at steady state including area under the plasma concentration-time curve from time 0 to 12 h (AUC (0-12)) and Cmax. |
Countries
United States
Outcome results
None listed