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.

Figure 1

Structure and primary metabolic pathways of prasugrel.

Figure 2

Serum concentration-time profiles of Pras-AM following different doses of prasugrel. (A) Serum concentrations after prasugrel LD of 60 mg and 30 mg on d 1. (B) Serum concentrations following prasugrel MD of 10, 7.5, and 5 mg on d 11. Data are presented as mean±SD. n=12. LD, loading dose; MD, maintenance dose.

Figure 3

Individual estimates of the area under the serum concentration-time curve from time of dosing through 4 h postdose for prasugrel active metabolite, Pras-AM, across a dose range of 5 mg to 60 mg of prasugrel. AUC_0–4, area under the curve through 4 h postdose.

Figure 4

Arithmetic mean VerifyNow P2Y₁₂ (VN-P2Y₁₂) percent inhibition of P2Y₁₂ reaction units (%IPRU) following a prasugrel loading dose and during prasugrel maintenance dose (MD).