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

• Published in: PloS one Vol. 10; no. 10; p. e0139862
• Main Authors: Hu, Chaoying, Tompson, Debra, Magee, Mindy, Chen, Qian, Liu, Yan Mei, Zhu, Wenjing, Zhao, Hongxin, Gross, Annette S., Liu, Yun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.10.2015; Public Library of Science (PLoS)
• Subjects: 1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors; 1-Alkyl-2-acetylglycerophosphocholine Esterase - metabolism; Adult; Approximation; Asian Continental Ancestry Group; Atherosclerosis; Benzaldehydes - administration & dosage; Benzaldehydes - adverse effects; Benzaldehydes - pharmacokinetics; Cardiovascular disease; China; Citrus paradisi; Clinical trials; Cultural differences; Diabetes; Diarrhea; Dosage; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Edema; Enzyme inhibitors; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacokinetics; Enzymes; Exposure; Family medical history; Female; Healthy Volunteers; Hospitals; Humans; Life assessment; Lipoproteins; Male; Metabolism; Metabolites; Oximes - administration & dosage; Oximes - adverse effects; Oximes - pharmacokinetics; Pharmacodynamics; Pharmacokinetics; Pharmacology; Phospholipase; Phospholipase A2; Prescription drugs; R&D; Research & development; Rhinopharyngitis; Safety; Steady state; Urine; China; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0139862

Darapladib is a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects. 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. 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. 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. ClinicalTrials.gov NCT02000804.