PHARMACOKINETICS Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers L. Vlase* PhD, M. Neag MBBS, A. Popa PhD, D. Muntean* PhD, I. Ba ˆldeaà PhD and S. E. Leucuta* PhD *Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, University of Medicine and Pharmacy ‘‘Iuliu Hatieganu’’, Cluj-Napoca,  Faculty of Pharmacy, Department of Clinical Pharmacy, University of Medicine and Pharmacy ‘‘Iuliu Hatieganu’’, Cluj-Napoca, and à‘‘Babes ¸ -Bolyai’’ University, Faculty of Chemistry and Chemical Engineering, Department of Physical-Chemistry, Cluj- Napoca, Romania SUMMARY What is known and Objective: Ivabradine is a novel heart rate-lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmaco- kinetic interaction between ivabradine and carbamazepine in healthy volunteers. Methods: The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12-h period following drug administra- tion, using a high-throughput liquid chromatog- raphy with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non-compartmental and com- partmental analysis to determine if there were statistically significant differences. Results and Discussion: In the two periods of treatments, the mean peak plasma concentrations (C max ) were 16Æ25 ng ⁄ mL (ivabradine alone) and 3Æ69 ng ⁄ mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C max , t max , were 0Æ97 and 1Æ14 h, respectively, and the total areas under the curve (AUC 0-¥ ) were 52Æ49 and 10Æ33 ng h ⁄ mL, respectively. These differ- ences were statistically significant for C max and AUC 0-¥ when ivabradine was administered with carbamazepine, whereas they were not for t max , half-life and mean residence time. What is new and Conclusion: TCarbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likley to be clinically significant. Keywords: carbamazepine, drug interaction, ivabradine, pharmacokinetics WHAT IS KNOWN AND OBJECTIVE Ivabradine is a novel heart rate-lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Its activity provides pure heart rate reduction at rest and during exercise. This improves myocardial oxygen balance and increa- ses coronary perfusion, without any significant influence on conduction, contractility, ventricular repolarization or blood pressure. The anti-ische- mic efficacy and the safety of ivabradine have Received 04 December 2009, Accepted 01 February 2010 Correspondence: Laurian Vlase, Faculty of Pharmacy, Depart- ment of Pharmaceutical Technology and Biopharmaceutics, University of Medicine and Pharmacy ‘‘Iuliu Hatieganu’’, Emil Isac 13, RO-400023 Cluj-Napoca, Romania. Tel. ⁄ Fax: +40264 595 770; e-mail: Laurian.Vlase@umfcluj.ro Journal of Clinical Pharmacy and Therapeutics (2011) 36, 225–229 doi:10.1111/j.1365-2710.2010.01170.x Ó 2010 Blackwell Publishing Ltd 225