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Mechanism Of Action
Vorapaxar is a reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, but its long half-life makes it effectively irreversible. Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation in in vitro studies. Vorapaxar does not inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen or a thromboxane mimetic and does not affect coagulation parameters ex vivo. PAR-1 receptors are also expressed in a wide variety of cell types, including endothelial cells, neurons, and smooth muscle cells, but the pharmacodynamic effects of vorapaxar in these cell types have not been assessed.
At 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 Pharmacokinetics].
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.
Evaluation of Vorapaxar on QTc Interval
The effect of vorapaxar on the QTc interval was evaluated 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.
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.
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.
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.
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.
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 Pharmacodynamics].
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 and Use In Specific Populations].
Figure 2: Effect of Intrinsic Factors on the
Pharmacokinetics of Vorapaxar
[see also DRUG INTERACTIONS]
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 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 and Figures 3 and 4]. The pharmacokinetic interaction between vorapaxar and clopidogrel has not been evaluated. 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 and Clinical Studies].
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
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/reference). Vorapaxar is a weak inhibitor of the intestinal P-glycoprotein (P-gp) transporter. No dosage adjustment of digoxin or ZONTIVITY is required.
Figure 4: Effects of Vorapaxar on the Pharmacokinetics
of Other Drugs
Vorapaxar did not increase bleeding time in non-human primates when administered alone. Bleeding time was prolonged slightly with administration of aspirin or aspirin plus vorapaxar. The combination of aspirin, vorapaxar, and clopidogrel produced significant prolongation of bleeding time. Transfusion of human platelet rich plasma normalized bleeding times with partial recovery of ex vivo platelet aggregation induced with arachidonic acid, but not induced with ADP or TRAP. Platelet poor plasma had no effect on bleeding times or platelet aggregation [see WARNINGS AND PRECAUTIONS].
The clinical evidence for the effectiveness of ZONTIVITY is supported by TRA 2°P - TIMI 50. TRA 2°P was a multicenter, randomized, double-blind, placebo-controlled study conducted in patients who had evidence or a history of atherosclerosis involving the coronary (spontaneous MI ≥ 2 weeks but ≤ 12 months prior), cerebral (ischemic stroke), or peripheral vascular (documented peripheral arterial disease [PAD]) systems. Patients were randomized to receive daily treatment with ZONTIVITY (n=13,225) or placebo (n=13,224) in addition to standard of care. The study's primary endpoint was the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR). The composite of cardiovascular death, MI, and stroke was assessed as key secondary endpoint. The median follow-up was 2.5 years (up to 4 years).
The findings in all randomized patients for the primary efficacy composite endpoint show a 3-year K-M event rate of 11.2% in the ZONTIVITY group compared to 12.4% in the placebo group (hazard ratio [HR]: 0.88; 95% confidence interval [CI], 0.82 to 0.95; p=0.001).
The findings for the key secondary efficacy endpoint show a 3-year Kaplan-Meier (K-M) event rate of 9.3% in the ZONTIVITY group compared to 10.5% in placebo group (HR 0.87; 95% CI, 0.80 to 0.94; p < 0.001).
Although TRA 2°P was not designed to evaluate the relative benefits and risks of ZONTIVITY in individual patient subgroups, patients with a history of stroke or TIA showed an increased risk of ICH. Of the patients who comprised the post-MI and PAD strata and had no baseline history of stroke or TIA,10,080 were randomized to treatment with ZONTIVITY and 10,090 to placebo. These patients were 89% Caucasian, 22% female, and 33% ≥ 65 years of age, with a median age of 60 years. The population included patients with diabetes (24%) and patients with hypertension (65%). Of the patients who qualified for the trial with MI without a history of stroke or TIA, 98% were receiving aspirin, 78% were receiving a thienopyridine, and 77% were receiving both aspirin and a thienopyridine when they enrolled in the trial. Of the patients who qualified for the trial with PAD without a history of stroke or TIA, 88% were receiving aspirin, 35% were receiving a thienopyridine, and 27% were receiving both aspirin and a thienopyridine when they enrolled.
In post-MI or PAD patients without a history of stroke or TIA the 3-year K-M event rate for the primary efficacy endpoint (composite of time to first CV death, MI, stroke, or UCR) was 10.1% in the ZONTIVITY group compared to 11.8% in the placebo group (HR 0.83; 95% CI, 0.76 to 0.90; p < 0.001) (see Figure 5 and Table 3).
The results for the key secondary efficacy endpoint (composite of time to first CV death, MI, or stroke) show a 3-year K-M event rate of 7.9% in the ZONTIVITY group compared to 9.5% in the placebo group (HR 0.80; 95% CI, 0.73 to 0.89; p < 0.001) (see Table 3).
The effect of chronic dosing with ZONTIVITY on the primary and key secondary endpoints was maintained for the duration of the trial (median follow up 2.5 years, up to 4 years).
Figure 5: Time to First
Occurrence of the Composite Endpoint of CV Death, MI, Stroke or UCR in Post-MI
or PAD Patients without a History of Stroke or TIA in TRA 2°P
Table 3: TRA 2°P: Time to
First Event in Post-MI or PAD Patients without a History of Stroke or TIA
|Endpoints||Placebo (n=10,090)||ZONTIVITY (n=10,080)||Hazard Ratio‡,§ (95% CI)||p-value§|
|Patients with events* (%)||K-M %†||Patients with events* (%)||K-M %†|
|Primary Composite Efficacy Endpoint (CV death/MI/stroke/UCR)*§||1073 (10.6%)||11.8%||896 (8.9%)||10.1%||0.83 (0.76-0.90)||< 0.001|
|Secondary Composite Efficacy Endpoint (CV death/MI/stroke)*,§||851 (8.4%)||9.5%||688 (6.8%)||7.9%||0.80 (0.73-0.89)||< 0.001|
|Other Secondary Efficacy Endpoints (first occurrences of specified event at any time) ¶|
|CV Death||239 (2.4%)||2.8%||205 (2.0%)||2.4%||0.86 (0.71-1.03)|
|MI||569 (5.6%)||6.4%||470 (4.7%)||5.4%||0.82 (0.73-0.93)|
|Stroke||145 (1.4%)||1.6%||98 (1.0%)||1.2%||0.67 (0.52-0.87)|
|UCR||283 (2.8%)||3.0%||249 (2.5%)||2.8%||0.88 (0.74-1.04)|
|* Each patient was counted only
once (first component event) in the component summary that contributed to the
primary efficacy endpoint.
† K-M estimate at 1,080 days.
‡ Hazard ratio is ZONTIVITY group versus placebo group.
§Cox proportional hazard model with covariates treatment and stratification factors (qualifying atherosclerotic disease and planned thienopyridine use).
¶Including patients who could have had other non-fatal events or subsequently died.
In post-MI or PAD patients who survived an on-study efficacy event, the incidence of subsequent events was lower with ZONTIVITY.
The time from the prior MI to randomization had no relationship to the treatment benefit for the primary study outcome.
A range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcomes as shown in Figure 6. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.
Figure 6: Subgroup Analyses (Primary Endpoints) of the
TRA 2°P Post-MI or PAD Patients without a History of Stroke or TIA
Last reviewed on RxList: 5/6/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Zontivity Information
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