teady-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
ZONTIVITY (Page 3 of 5)
By Merck Sharp & Dohme Corp. | Last revised: 8 May 201412.2 PharmacodynamicsAt the recommended dose, ZONTIVITY achieves ≥80% inhibition of TRAP-induced platelet aggregation within one week of initiation of treatment. The duration of platelet inhibition is dose- and concentration-dependent. Inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected at 4 weeks after discontinuation of daily doses of ZONTIVITY 2.08 mg, consistent with the terminal elimination half-life of vorapaxar [see Clinical Pharmacology (12.3)].
In healthy volunteer studies, no changes in platelet P-selectin and soluble CD40 ligand (sCD40L) expression or coagulation test parameters (TT, PT, aPTT, ACT, ECT) occurred after single- or multiple- dose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L, or hs-CRP concentrations were observed in patients treated with vorapaxar in the phase 2/3 clinical trials.
eva luation of Vorapaxar on QTc Interval
The effect of vorapaxar on the QTc interval was eva luated in a thorough QT study and in other studies. Vorapaxar had no effect on the QTc interval at single doses up to 48 times the recommended dose.
12.3 PharmacokineticsVorapaxar exposure increases in an approximately dose-proportional manner following single doses up to 16 times the recommended dose. Vorapaxar pharmacokinetics are similar in healthy subjects and patients.
Absorption
After oral administration of a single ZONTIVITY 2.08 mg dose under fasted conditions, peak concentrations (Cmax ) occur at 1 hour post-dose (range: 1 to 2 h). The mean absolute bioavailability as determined from a microdosing study is approximately 100%.
Ingestion of vorapaxar with a high-fat meal resulted in no meaningful change in AUC with a small (21%) decrease in Cmax and delayed time to peak concentration (45 minutes). ZONTIVITY may be taken with or without food.
Distribution
The mean volume of distribution of vorapaxar is approximately 424 liters (95% CI: 351-512). Vorapaxar and the major circulating active metabolite, M20, are extensively bound (≥99%) to human plasma proteins. Vorapaxar is highly bound to human serum albumin and does not preferentially distribute into red blood cells.
Metabolism
Vorapaxar is eliminated by metabolism via CYP3A4 and CYP2J2. The major active circulating metabolite is M20 (monohydroxy metabolite) and the predominant metabolite identified in excreta is M19 (amine metabolite). The systemic exposure of M20 is ~20% of the exposure to vorapaxar.
Excretion
The primary route of elimination is through the fe |
