Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants

Abstract

Aims: This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel.

Methods: Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)].

Results: Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001).

Conclusions: Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.

Figure 1

Prasugrel and clopidogrel metabolic pathways to their active metabolites

Figure 2

Study design and patient disposition. Ninety subjects received ≥1 dose of study drug. In period 1, 45 subjects completed 10 days of prasugrel and 41 subjects completed 10 days of clopidogrel. In period 2, 43 subjects completed 10 days of clopidogrel and 40 subjects completed 10 days of prasugrel. Clop, clopidogrel; n, number of subjects; Pras, prasugrel

Figure 3

Mean plasma concentration of Pras-AM and Clop-AM (day 10) by CYP2C19-predicted phenotype. Clop-AM, clopidogrel active metabolite, CYP, cytochrome P450; RM, rapid metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; Pras-AM, prasugrel active metabolit. Prasugrel RM (); Clopidogrel RM (); Prasugrel IM (); Clopidogrel IM (); Prasugrel PM (); Clopidogrel PM ()

Figure 4

Mean platelet aggregation as assessed by LTA IPA to 20 µM ADP (A), VN P2Y12 assay (B) and VASP phosphorylation (C) following daily doses of 10 mg prasugrel and 75 mg clopidogrel according to CYP2C19-predicted phenotype. Differences in IPA (A) between prasugrel and clopidogrel were statistically significant (P < 0.05) at all time points. ADP, adenosine diphosphate; CYP, cytochrome P450; RM, rapid metabolizer; IM, intermediate metabolizer; IPA, inhibition of platelet aggregation; LTA, light transmittance aggregometry; PM, poor metabolizer; PRI, platelet reactivity index; PRU, P2Y₁₂ reactivity units; VASP, vasodilator-stimulated phosphoprotein; VN, Accumetrics VerifyNow™. Prasugrel RM (); Clopidogrel RM (); Prasugrel IM (); Clopidogrel IM (); Prasugrel PM (); Clopidogrel PM ()

Figure 5

Pharmacokinetic and pharmacodynamic responses to clopidogrel and prasugrel in individual subjects on day 10 following daily doses of 10 mg prasugrel and 75 mg clopidogrel stratified by predicted CYP2C19 phenotype. Panel A shows active metabolite exposure, which is consistently higher for prasugrel than for clopidogrel across all 3 groups. Inhibition of platelet aggregation as measured by LTA (B), VN P2Y12 assay (C), and VASP phosphorylation (D) is also shown. The asterisked RM subject in panels B and C is subject 169, who was very likely noncompliant during prasugrel treatment. See text (Pharmacodynamic results) for details. AUC, area under the plasma concentration–time curve; ADP, adenosine diphosphate; Clop-AM, clopidogrel's active metabolite; CYP, cytochrome P450; RM, rapid metabolizer; IM, intermediate metabolizer; IPA, inhibition of platelet aggregation; LTA, light transmittance aggregometry; PM, poor metabolizer; Pras-AM, prasugrel's active metabolite; PRI, platelet reactivity index; PRU, P2Y₁₂ reactivity units; VASP, vasodilator-stimulated phosphoprotein; VN, Accumetrics VerifyNow™

Figure 5

Pharmacokinetic and pharmacodynamic responses to clopidogrel and prasugrel in individual subjects on day 10 following daily doses of 10 mg prasugrel and 75 mg clopidogrel stratified by predicted CYP2C19 phenotype. Panel A shows active metabolite exposure, which is consistently higher for prasugrel than for clopidogrel across all 3 groups. Inhibition of platelet aggregation as measured by LTA (B), VN P2Y12 assay (C), and VASP phosphorylation (D) is also shown. The asterisked RM subject in panels B and C is subject 169, who was very likely noncompliant during prasugrel treatment. See text (Pharmacodynamic results) for details. AUC, area under the plasma concentration–time curve; ADP, adenosine diphosphate; Clop-AM, clopidogrel's active metabolite; CYP, cytochrome P450; RM, rapid metabolizer; IM, intermediate metabolizer; IPA, inhibition of platelet aggregation; LTA, light transmittance aggregometry; PM, poor metabolizer; Pras-AM, prasugrel's active metabolite; PRI, platelet reactivity index; PRU, P2Y₁₂ reactivity units; VASP, vasodilator-stimulated phosphoprotein; VN, Accumetrics VerifyNow™