ces. In a 6-week study, 84% of the administered radiolabeled dose was recovered as total radioactivity with 58% collected in feces and 25% in urine. Vorapaxar is eliminated primarily in the form of metabolites, with no unchanged vorapaxar detected in urine.
Vorapaxar exhibits multi-exponential disposition with an effective half-life of 3-4 days and an apparent terminal elimination half-life of 8 days. Steady-state is achieved by 21 days following once-daily dosing with an accumulation of 5- to 6-fold. The apparent terminal elimination half-life for vorapaxar is approximately 8 days (range 5-13 days) and is similar for the active metabolite. The terminal elimination half-life is important to determine the time to offset the pharmacodynamic effect [see Clinical Pharmacology (12.2)].
Specific Populations
The effects of intrinsic factors on the pharmacokinetics of vorapaxar are presented in Figure 2 [see Use in Specific Populations (8.5, 8.6, 8.7)].
In general, effects on the exposure of vorapaxar based on age, race, gender, weight, and moderate renal insufficiency were modest (20-40%; see Figure 2). No dose adjustments are necessary based upon these factors. Because of the inherent bleeding risks in patients with severe hepatic impairment, ZONTIVITY is not recommended in such patients [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].
Figure 2: Effect of Intrinsic Factors on the Pharmacokinetics of Vorapaxar
See Warnings and Precautions. (5.1) and Use in Specific Populations. (8.7)
(click image for full-size original)
Drug Interactions [see also Drug Interactions (7)]
Anticoagulants and Antiplatelet Agents
An interaction study with vorapaxar and warfarin in healthy subjects did not demonstrate a clinically significant pharmacokinetic or pharmacodynamic interaction [see Warnings and Precautions (5.1) and Figure 4].
Vorapaxar did not affect prasugrel pharmacokinetics and prasugrel did not affect vorapaxar pharmacokinetics following multiple-dose administration at steady-state [see Warnings and Precautions (5.1) and Figures 3 and 4]. The pharmacokinetic interaction between vorapaxar and clopidogrel has not been eva luated. However, the use of vorapaxar on a background of clopidogrel is supported by the clinical data from TRA 2°P and TRA•CER [see Adverse Reactions (6.1) and Clinical Studies (14)].
Effects of Other Drugs on Vorapaxar
The effects of other drugs on the pharmacokinetics of vorapaxar are presented in Figure 3 as change relative to vorapaxar administered alone (test/reference). Phase 3 data suggest that coadministration of a weak or moderate CYP3A inhibitor with vorapaxar does not increase bleeding risk or alter the efficacy of vorapaxar. No dose adjustment for ZONTIVITY is required in patients taking weak to moderate inhibitors of CYP3A.
Figure 3: Effects of Other Drugs on the Pharmacokinetics of Vorapaxar
See Warnings and Precautions. (5.2) and Drug Interactions. (7.1)
See Dosage and Administration. (2.2)
Effects of Vorapaxar on Other Drugs
In vitro metabolism studies demonstrate that vorapaxar or M20 is unlikely to cause clinically significant inhibition or induction of major CYP isoforms or inhibition of OATP1B1, OATP1B3, BCRP, OAT1, OAT3, and OCT2 transporters.
Specific in vivo effects on the pharmacokinetics of digoxin, warfarin, rosiglitazone and prasugrel are presented in Figure 4 as a change relative to the interacting drug administered alone (test/referen |
