Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects

Abstract

Aim: To characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and tolerability of different dose regimens of prasugrel in healthy Chinese subjects. Methods: This was a single-centered, open-label, parallel-design study. Subjects received a single loading dose (LD) of prasugrel followed by once-daily maintenance dose (MD) for 10 d. They were enrolled into 3 groups: 60 mg LD/10 mg MD; 30 mg LD/7.5 mg MD; 30 mg LD/5 mg MD. Blood samples were collected after the first and last dose. The serum concentration of the active metabolite of prasugrel was determined using a LC/MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y 12 assay. Results: Thirty-six healthy native Chinese subjects (19 males) aged 18-45 were enrolled; mean age and body weight were similar across the treatment groups (n=12 for each). The metabolite AUC 0-4 and C max increased dose-proportionally across the dose range of 5 mg to 60 mg. The median T max was 0.5 h in all groups. The PD parameters, indicated by the inhibition of ADP-induced platelet aggregation, were met more rapidly in the 60 mg group than the 30 mg group after the LD (94%-98%). This high degree of inhibition of platelet aggregation was maintained following the 10 mg MD (87%-90%) and was lower in the 7.5 mg and 5 mg MD groups (79%-83% and 64%-67%, respectively). Prasugrel was well tolerated in healthy Chinese subjects for single doses up to 60 mg and a MD of 10 mg for 10 d. Conclusion: The PKs and PDs of the active metabolite of prasugrel were similar to those in Chinese subjects reported by a previous bridging study, which demonstrated that the exposure to the active metabolite in Chinese subjects was higher than in Caucasians.

World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI

“…38 The higher exposure of the prasugrel active metabolite in East Asian individuals than in white patients translates into the pharmacodynamic profile. [36][37][38][39][40][41][42] In a single-centre study of healthy volunteers, the level of inhibition of platelet aggregation induced by 20 μmol/l ADP in East Asian individuals taking 5 mg of prasugrel daily did not differ from that in white individuals taking 10 mg of p rasugrel daily (mean value at 4 h last-dose: 68.9% vs 70.1%). 40 In Japanese patients undergoing PCI, 15 mg loading and 3.75 mg maintenance doses of prasugrel achieved a faster, higher, and more-consistent antiplatelet effect than 300 mg loading and 75 mg maintenance doses of clopidogrel.…”

“…In individual studies, the level of the prasugrel active metabolite was 30-47% higher in East Asian patients than in white patients after loading and maintenance doses. [36][37][38][39][40] After adjusting for body mass, active metabolite exposure was still 19% higher in East Asian patients than in white patients, 40 and this finding was more prominent (45-56% higher) in patients with a low body mass (<60 kg). 38 The higher exposure of the prasugrel active metabolite in East Asian individuals than in white patients translates into the pharmacodynamic profile.…”

Candidate gene and pathway analyses identifying genetic variations associated with prasugrel pharmacokinetics and pharmacodynamics

“…The study was conducted in compliance with the Declaration of Helsinki. Detailed inclusion and exclusion criteria and the study design have been published previously [42].…”

Hormonal, chemical and thermal inhibition of spermatogenesis: contribution of French teams to international data with the aim of developing male contraception in France

“…The question arises through observations regarding other pharmacological compounds that seemed more active in Chinese than in Caucasian subjects at similar doses [56]. …”