as 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 Pharmacokinetics
Vorapaxar 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
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 feces. 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)
Drug Interactions [see also Drug Interactions (7)]
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 s |
