Pharmacokinetic interaction between ivabradine and phenytoin in healthy subjects

Abstract

Background: Phenytoin is an inductor of the main metabolizing enzyme of ivabradine and it could influence its pharmacokinetics. Changes in ivabradine pharmacokinetics could have clinical significance regarding the safety of the treatment.

Objective: The study objective was evaluation of the pharmacokinetic interaction between ivabradine and phenytoin in healthy subjects.

Methods: A single dose of ivabradine 10 mg was administered alone or in combination with phenytoin 150 mg to 18 healthy subjects in a two-treatment study design, separated by 5 days in which the phenytoin alone was administered at a dose of 150 mg twice daily. Plasma concentrations of ivabradine were determined during a 12-hour period following drug administration, using a high-throughput liquid chromatography coupled with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment were calculated using non-compartmental analysis and compared to determine if the differences were statistically significant.

Results: In the two treatment periods, the mean ± SD peak plasma concentrations (C(max)) were 18.6 ± 8.0 ng/mL (ivabradine alone) and 6.5 ± 3.1 ng/mL (ivabradine after pre-treatment with phenytoin). The mean ± SD times taken to reach C(max) (t(max)) were 1.2 ± 0.7 h and 0.8 ± 0.6 h, respectively, and the total areas under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were 62.3 ± 18.7 ng · h/mL and 19.2 ± 17.0 ng · h/mL, respectively. Statistically significant differences were observed for the C(max) and AUC(∞) of ivabradine when administered alone or with phenytoin, whereas for t(max) and the half-life the differences were non-significant.

Conclusion: This study showed that phenytoin has an important effect on the pharmacokinetics of ivabradine in healthy subjects, reducing its bioavailability by approximately 70%.