Atherosclerosis
Conditions
Keywords
Darapladib, Safety, Pharmacokinetics, Pharmacodynamics, Healthy Chinese Subjects
Brief summary
This study is to evaluate pharmacokinetics (PK), pharmacodynamics (PD) and safety of 160 mg enteric-coated micronised free base darapladib in healthy Chinese subjects.
Detailed description
SB-480848 (darapladib) is a novel selective and orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) being developed by GlaxoSmithKline (GSK) for the treatment of atherosclerosis. This will be an open label study where each Subject will participate in 2 study sessions, a single dose session and a repeat dose session. All Subjects will receive 160 mg of enteric coated micronised free-base darapladib as a single dose and as repeated daily doses for 28 days. The purpose of this study is to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) and safety of single and repeat oral dose of darapladib in healthy Chinese Subjects. The primary endpoints for safety are: clinical safety data from spontaneous adverse event reporting, 12-lead electrocardiogram recording, vital sign measurement, nursing/physician observation and clinical laboratory tests. The primary PK parameters of interest are area under plasma concentration time curve (AUC) and maximum plasma concentration (Cmax) of darapladib, while the secondary PK parameters of interest are: time of occurrence of Cmax (Tmax) and apparent terminal phase half-life (t1/2) of darapladib as well as AUC, Cmax, Tmax and t1/2 of the metabolite, SB-553253. Finally, the PD endpoint of interest is plasma Lp PLA2 activity, as expressed in terms of percent inhibition relative to baseline.
Interventions
DRUGdarapladib 160mg
drug
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy Chinese males or females aged between 18 and 45 years of age inclusive, at the time of signing the informed consent. (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 parameters 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 if required) agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. ) * Of Chinese origin - defined as being born in mainland China, having four ethnic Chinese grandparents. * Body weight ≥50 kg and BMI within the range 19 to 24 kg/m2 (inclusive). * A female Subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy \[for this definition, documented refers to the outcome of the investigator's/designee's review of the Subject's medical history for study eligibility, as obtained via a verbal interview with the Subject or from the Subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \>40 MlU/ml and estradiol \< 40 pg/ml (\<147 pmol/L) is confirmatory\]. Child-bearing potential with negative pregnancy test as determined by urine human chorionic gonadotropin (hCG) test at screening or prior to dosing and Agrees to use 1 of the contraception methods listed in Section 4.3.1 from the time of Screening to sufficiently minimize the risk of pregnancy at that point. Female Subjects must agree to use contraception until the follow-up contact. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form * Alanine aminotransferase (ALT), alkaline phosphatise (ALP) and bilirubin ≤1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * Based on single or averaged QTc values of triplicate ECGs obtained over a brief recording period: QT duration corrected for heart rate by Bazett's formula (QTcB) or QT duration corrected for heart rate by Fridericia's formula (QTcF) \<450 msec; QTc \<480 msec in Subjects with Bundle Branch Block.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ro for darapladib | Up to 12 weeks | Accumulation ratios Cmax accumulation ratio |
| Adverse event | Up to 12 weeks | An AE is any untoward medical occurrence in a patient or clinical investigation Subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| 12-lead ECG | Up to 12 weeks | 12-lead ECGs will be obtained at designated timepoint during the study, using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. |
| Vital sign measurement | Up to 12 weeks | Systolic and diastolic blood pressure and pulse rate |
| clinical laboratory examination | Up to 12 weeks | Hematology, clinical chemistry, urinalysis and additional parameters to be tested |
| AUC0-t for darapladib | Up to 12 weeks | Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration |
| AUC 0-∞ for Darapdlib | Up to 12 weeks | Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time |
| Cmax for darapladib | Up to 12 weeks | Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time |
| Rcmax for darapladib | Up to 12 weeks | Accumulation ratios Cmax accumulation ratio |
| Nursing/physician observation | Up to 12 weeks | The physical examination will include assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| T1/2 for darapladib | Up to 12 weeks | Terminal phase half-life for darapladib |
| AUC0-t for darapladib metabolite SB-553253 (as data permit). | Up to 12 weeks | Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration for the pharmacologically active metabolite SB-553253 |
| AUC0-∞ for darapladib metabolite SB-553253 (as data permit). | Up to 12 weeks | Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time the pharmacologically active metabolite SB-553253 |
| Cmax for darapladib metabolite SB-553253 (as data permit). | Up to 12 weeks | Maximum observed concentration for the pharmacologically active metabolite SB-553253 |
| T1/2 for darapladib metabolite SB-553253 (as data permit). | Up to 12 weeks | Terminal phase half-life for the pharmacologically active metabolite SB-553253 |
| Tmax for darapladib metabolite SB-553253 (as data permit). | Up to 12 weeks | Time of occurrence of Cmax for the pharmacologically active metabolite SB-553253 |
| Plasma Lp-PLA2 activity | Up to 12 weeks | Percent inhibition relative to baseline of Plasma Lp-PLA2 |
| Tmax for darapladib | Up to 12 weeks | Time of occurrence of Cmax for darapladib |
Countries
China
Outcome results
None listed