Abstract
Background and ObjectivesDarapladib is a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects.MethodsTwenty-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.ResultsSystemic 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.ConclusionDarapladib 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 RegistrationClinicalTrials.gov NCT02000804
Highlights
Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme produced and secreted by inflammatory cells, has the potential to be a novel target for the treatment of atherosclerosis [1,2,3] among other indications
This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects
The steady-state accumulation ratio was less than unity (Rs = 0.80), indicating time-dependent pharmacokinetics of darapladib
Summary
Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme produced and secreted by inflammatory cells, has the potential to be a novel target for the treatment of atherosclerosis [1,2,3] among other indications. Darapladib is a first-in-class orally active, selective, reversible inhibitor of the Lp-PLA2 enzyme that is currently being developed for the treatment of atherosclerosis [4] and diabetic macular edema [5]. Consistent with Class 4 BCS products, the absolute bioavailability of oral darapladib is low (4% for darapladib enteric coated tablet [Unpublished data] and 12% for a solution [6]). Compared with the fasted state, administration of a high fat meal with darapladib enteric coated tablet resulted in a 19% increase in systemic exposure (AUC) to darapladib and the higher exposure is not considered to be clinically relevant [Unpublished data]. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects.
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