Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of the Novel Lipoprotein-Associated Phospholipase A2 Enzyme Inhibitor Darapladib in Healthy Chinese Subjects: An Open Label Phase-1 Clinical Trial

Abstract

Background and objectives: Darapladib is a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects.

Methods: Twenty-four subjects received darapladib 160 mg orally, approximately 1 hour after a standard breakfast, as a single dose and once daily for 28 days. Non-compartmental methods were used to determine the single and multiple dose pharmacokinetics of darapladib and its metabolite SB-553253. Repeat dose Lp-PLA2 activity and safety were evaluated.

Results: Systemic exposure (AUC(0-T), Cmax geometric mean (CVb%)) of darapladib was higher after multiple-dosing (519 ng.h/mL (33.3%), 34.4 ng/mL (49.9%)) compared to single-dose administration (153 ng.h/mL (69.0%), 17.9 ng/mL (55.2%). The steady-state accumulation ratio was less than unity (Rs = 0.80), indicating time-dependent pharmacokinetics of darapladib. Darapladib steady-state was reached by Day 14 of once daily dosing. Systemic exposure to SB-553253 was lower than darapladib with median (SB-553253: darapladib) ratios for AUC(0-τ) of 0.0786 for single dose and 0.0532 for multiple dose administration. On Day 28, pre-dose and maximum inhibition of Lp-PLA2 activity was approximately 70% and 75% relative to the baseline value, respectively and was dependent of darapladib concentration. The most common adverse events (≥ 21% subjects) were abnormal faeces, abnormal urine odour, diarrhoea and nasopharyngitis.

Conclusion: Darapladib 160 mg single and repeat doses were profiled in healthy Chinese subjects. Single dose systemic exposure to darapladib in healthy Chinese subjects was consistent with that observed previously in Western subjects whereas steady-state systemic exposure was approximately 65% higher in Chinese than Western subjects. The Lp-PLA2 activity and adverse event profile were similar in healthy Chinese and previous reports in Western subjects. Ethnic-specific dose adjustment of darapladib is not considered necessary for the Chinese population.

Trial registration: ClinicalTrials.gov NCT02000804.

Conflict of interest statement

Competing Interests: DT, MM, WZ and AG are GlaxoSmithKline employees and own GSK stock. HZ is a GSK employee. CH, QC, YML and YL have no conflicts of interests to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Subject disposition flow diagram where n is number of subjects in each category.

Fig 2. Median concentration-time profiles of darapladib following single and multiple dose administration over a period of 96 hours on linear-linear scale (A) and log- linear scale (B) truncated at 96 hours and (C) log-linear to the final observation.

Fig 3. Plasma darapladib concentration versus Lp-PLA2 activity v after multiple dose of darapladib.

Data points are indicated by symbols and the Emax relationship fitted is represented by the red line.

Fig 4. Darapladib single dose AUC(0-∞) relative to repeat dose AUC(0–24) in individual healthy Chinese and Western healthy subjects.