Fengjuan Xuan

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 AUC0–24 h and Cmax by approximately twofold (GMR [90% CI]: 196% [173,222]; 193% [166,223], respectively), while rifampin decreased vorapaxar AUC0–24 h and Cmax 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.

Effect of the thrombin receptor antagonist (PAR-1) vorapaxar on QT/QTc interval in healthy volunteers: A randomized, placebo- and positive-controlled, parallel group trial

In a randomized, double‐blind (vorapaxar and placebo), placebo‐ and positive‐controlled (moxifloxacin 400 mg) parallel group study, the effect of single‐dose vorapaxar 120 mg on QT/QTc interval was assessed in 120 adults 18–50 years. Twelve‐lead digital ECGs were obtained in triplicate using Mortara H12+ Holter monitors at 9 timepoints over 24 hours. If the largest upper bound of the 95% one‐sided CI for the mean difference in QTcF between vorapaxar and placebo was <10 milliseconds, vorapaxar was considered to have no potential for QT/QTc prolongation of regulatory concern. Vorapaxar was well‐tolerated. The lower bound of the 95% CI for the difference in QTcF between moxifloxacin and placebo was >5 milliseconds, confirming study sensitivity. Vorapaxar had no significant effect on QTcF. At all timepoints the upper 95% CI for the mean difference between placebo and vorapaxar was ≤3.8 milliseconds (mean difference ≤1.0 milliseconds). Vorapaxar does not prolong the QT/QTc interval in healthy subjects.

Comparison of the systemic bioavailability of mometasone furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary disease

Background Coadministration of mometasone furoate (MF) and formoterol fumarate (F) produces additive effects for improving symptoms and lung function and reduces exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD). The present study assessed the relative systemic exposure to MF and characterized the pharmacokinetics of MF and formoterol in patients with COPD. Methods This was a single-center, randomized, open-label, multiple-dose, three-period, three-treatment crossover study. The following three treatments were self-administered by patients (n = 14) with moderate-to-severe COPD: MF 400 μg/F 10 μg via a metered-dose inhaler (MF/F MDI; DULERA®/ZENHALE®) without a spacer device, MF/F MDI with a spacer, or MF 400 μg via a dry-powder inhaler (DPI; ASMANEX® TWISTHALER®) twice daily for 5 days. Plasma samples for MF and formoterol assay were obtained predose and at prespecified time points after the last (morning) dose on day 5 of each period of the crossover. The geometric mean ratio (GMR) as a percent and the corresponding 90% confidence intervals (CI) were calculated for treatment comparisons. Results Systemic MF exposure was lower (GMR 77%; 90% CI 58, 102) following administration by MF/F MDI compared to MF DPI. Additionally, least squares geometric mean systemic exposures of MF and formoterol were lower (GMR 72%; 90% CI 61, 84) and (GMR 62%; 90% CI 52, 74), respectively, following administration by MF/F MDI in conjunction with a spacer compared to MF/F MDI without a spacer. MF/F MDI had a similar adverse experience profile as that seen with MF DPI. All adverse experiences were either mild or moderate in severity; no serious adverse experience was reported. Conclusion Systemic MF exposures were lower following administration by MF/F MDI compared with MF DPI. Additionally, systemic MF and formoterol exposures were lower following administration by MF/F MDI with a spacer versus without a spacer. The magnitude of these differences with respect to systemic exposure was not clinically relevant.

Effect of Food, Antacid, and Age on the Pharmacokinetics of the Oral Thrombin Receptor Antagonist Vorapaxar (SCH 530348) in Healthy Volunteers

This randomized, open‐label, parallel group study examined the effects of food, antacid, and age on the pharmacokinetics of vorapaxar. In total, 101 subjects were enrolled including 83 young adults (18–45 years) and 18 elderly subjects (>65 years). Subjects received single‐dose vorapaxar 40 mg after a 10‐hour fast (young and elderly) or with extra‐strength antacid, food, or 1 or 2 hours after food (young only). Vorapaxar 40 mg was rapidly absorbed after a fast (median Tmax: 1 hour). Administration with food or 1 or 2 hours post‐meal modestly increased vorapaxar mean area under the curve (AUC) and Cmax and prolonged median Tmax by 1 hour. Concomitant food modestly increased vorapaxar AUC from time zero to infinity [AUC(I)] and Cmax 43% and 31%, respectively. Antacid modestly decreased vorapaxar AUC(I) by 15% and Cmax by 38%, and increased median Tmax by 1 hour. Vorapaxar AUC(I) and Cmax were 41% and 29% higher, respectively, in elderly versus young subjects. Concomitant food and older age were associated with modest increases, and antacid was associated with a small decrease in vorapaxar exposure, which are not expected to affect the drugs safety or efficacy.

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.