Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone.

PURPOSE: To evaluate the potential effects of vorapaxar on the pharmacokinetics and safety of rosiglitazone. METHODS: This was an open-label, two-period, two-treatment, fixed-sequence study in 18 healthy subjects. On Day 1, Period 1, subjects received a single dose of rosiglitazone 8 mg. In Period 2, subjects received vorapaxar 40 mg on Day 1, vorapaxar 7.5 mg once-daily on Days 2-7, and a single dose of rosiglitazone 8 mg on Day 7. Rosiglitazone and N-desmethylrosiglitazone pharmacokinetics were assessed alone (Period 1) and after coadministration with vorapaxar (Period 2). Vorapaxar and its M20 metabolite pharmacokinetics were assessed on Day 7, Period 2. Safety and tolerability were assessed throughout the study. RESULTS: Coadministration of rosiglitazone with vorapaxar had no effect on rosiglitazone or N-desmethylrosiglitazone pharmacokinetics. The ratio of geometric means (GMR) and 90% confidence intervals (CI) of the coadministration versus monotherapy for Cmax (GMR 95; 90% CI 88, 103) and AUC0-24 h (GMR 103; 90% CI 98, 108) were within the 80-125% bioequivalence criteria. The metabolite-to-parent exposure ratio with and without vorapaxar was unaltered. Coadministration of vorapaxar with rosiglitazone was generally well tolerated. CONCLUSION: Coadministration of vorapaxar with rosiglitazone or drugs metabolized via CYP2C8 is unlikely to cause a significant pharmacokinetic interaction.

The effect of multiple doses of ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar.

This randomized, open-label, parallel-group study evaluated the effects of multiple-dose ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar. Healthy subjects randomly received one of the following three treatments (N = 12/group): (1) ketoconazole 400 mg once daily (QD) for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28); (2) rifampin 600 mg QD for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28); and (3) placebo QD for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28). Ketoconazole increased the steady-state vorapaxar AUC(0-24 h) and C(max) by approximately twofold (GMR [90% CI]: 196% [173,222]; 193% [166,223], respectively), while rifampin decreased vorapaxar AUC(0-24 h) and C(max) by approximately 50% (GMR [90% CI]: 45.5% [40,52]; 61.4% [52,72], respectively) versus vorapaxar alone. Potent CYP3A4 inhibitors or inducers may cause moderate increases or decreases in vorapaxar exposure, respectively, which may have safety and/or efficacy implications; therefore, their concomitant use with vorapaxar is not recommended.

The Influence of Multiple-Dose Vorapaxar, an Oral PAR-1 Receptor Antagonist, on the Single-Dose Pharmacokinetics and Pharmacodynamics of Digoxin.

Vorapaxar is a novel orally active thrombin receptor antagonist selective for the PAR-1 receptor. This open-label, single-center, fixed-sequence, 2-period, 2-treatment study assessed the pharmacokinetics and pharmacodynamics of single-dose digoxin in the presence/absence of multiple-dose vorapaxar. Eighteen healthy adult subjects received two treatments in a fixed sequence separated by ≥8-day washout: (A) digoxin 0.5 mg (Day 1); (B) vorapaxar 2.5 mg/day Days 1-6 and single-dose vorapaxar 40 mg administered with single-dose digoxin 0.5 mg Day 7. The geometric mean ratio (%; GMR) for the two treatments (digoxin alone and digoxin plus vorapaxar) and 90% confidence intervals (CIs) for and AUCtf and Cmax of digoxin were calculated. Pharmacodynamics of digoxin was assessed by measuring changes in electrocardiogram (ECG) parameters. The GMR (90% CIs) estimates for digoxin AUCtf and Cmax were 105% (91, 121) and 154% (130, 181), respectively. Except for differences in peak plasma concentrations, the pharmacokinetics of digoxin were similar between the two treatments. Coadministration of vorapaxar plus digoxin had no effect on digoxin Tmax or ECG parameters. The results of this study suggest that the coadministration of vorapaxar and digoxin is unlikely to cause a clinically significant drug-drug interaction.

Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment.

PURPOSE: To determine whether hepatic impairment has an effect on the pharmacokinetics (PK) of vorapaxar or M20, its main pharmacologically active metabolite. METHODS: This was an open-label study in which a single 40-mg oral dose of vorapaxar was administered to patients with mild (n = 6), moderate (n = 6), and severe (n = 4) hepatic impairment and healthy controls (n = 16) matched for age, gender, weight, and height. Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose. RESULTS: Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls. Group mean values for vorapaxar C(max) and AUC(tf) were 206-279 ng/mL and 14,200-18,200 ng·h/mL, respectively, with the lowest values observed in patients with severe impairment. Vorapaxar median T(max) and mean t(1/2) values were 1.00-1.75 h and 298-366 h, respectively. There was no apparent correlation between vorapaxar or M20 exposure or t(1/2) values and disease severity. Vorapaxar was generally well tolerated; one serious adverse event (gastrointestinal bleeding secondary to ruptured esophageal varices) was reported in a patient with severe hepatic impairment. CONCLUSIONS: Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20. No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment. Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment, administration of vorapaxar to such patients is not recommended given their bleeding diathesis.

Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease.

PURPOSE: To determine whether impaired renal function alters the pharmacokinetics (PK) of vorapaxar or its ability to inhibit thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. METHODS: This was an open-label study in which 8 patients with end-stage renal disease (ESRD) on hemodialysis and 7 matched (based on age, gender, weight, and height) healthy controls were administered a single 10-mg oral dose of vorapaxar. Blood samples for vorapaxar PK and pharmacodynamic analysis were collected predose and at frequent intervals up to 6 weeks postdose. RESULTS: Mean vorapaxar bioavailability (based on area under the curve of plasma vorapaxar concentration over time) was identical in the two subject groups; the ESRD/healthy geometric mean ratio (GMR, expressed in percent) was 98. Mean maximum observed plasma concentration (77.4-98.2 ng/mL) was numerically lower in patients with ESRD compared with matched controls (GMR=76; 90% confidence interval=48 to 118). Median time of maximum observed plasma concentration was 2 h in both subject groups. The observed means for elimination half-life were 186 and 231 h in the ESRD and control groups, respectively. Inhibition of platelet aggregation was similar in the two groups. Four out of 15 (27%) subjects reported adverse events, all of which were characterized by the investigator as mild and unrelated to treatment. CONCLUSIONS: ESRD had no clinically relevant effect on the PK profile of vorapaxar or its ability to inhibit TRAP-induced platelet aggregation.

Determination of a novel thrombin receptor antagonist (SCH 530348) in human plasma: evaluation of Ultra Performance Liquid Chromatography™-tandem mass spectrometry for routine bioanalytical analysis.

SCH 530348 is a safe and effective oral anti-platelet agent for patients with acute coronary syndrome. Clinical study results suggest that SCH 530348 dosage at 20 mg or 40 mg is feasible to achieve rapid maximum platelet inhibition following an acute coronary event or intervention procedure. To permit accurate determinations of circulating SCH 530348 in plasma following dosing, a method for measuring SCH 530348 concentrations in human plasma was validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method utilized semi-automated 96-well protein precipitation with gradient chromatography using an ACQUITY™ UPLC BEH C18 (2.1 mm×50 mm, 1.7 µm) column. The retention time of SCH 530348 was approximately 1.5 min. This method was validated for routine quantitation of SCH 530348 over the concentration range of 1.00-1000 ng/mL. Inter-run accuracy based on mean percent theoretical for replicate quality control samples was better than 95.2%. Inter-run precision based on percent relative deviation for replicate quality control samples was ≤3.3%. SCH 530348 quality control samples were stable in human plasma for up to three freeze/thaw cycles, for at least 467 days when frozen at -20 °C and for at least 7 h when stored at room temperature. The lower limit of quantitation was 1.00 ng/mL for a 100 µL plasma aliquot.