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Effects of Hypericum perforatum on Ivabradine Pharmacokinetics in Healthy Volunteers: An Open-Label, Pharmacokinetic Interaction Clinical Trial

From the Clinical Pharmacology Studies Unit, Clinical Pharmacology Service, Hospital Clínico San Carlos, Madrid, Spain (Dr Portolés, Dr Terleira, Dr Calvo); Laboratorios Servier, Madrid, Spain (Ms Martínez); and the Cardiovascular Division, Institut de Recherches Internationales Servier, Curbevoie Cedex, France (Dr Resplandy).

The effects of the CYP3A4 inducer, Hypericum perforatum, on the pharmacokinetics of a single oral dose of ivabradine were assessed. An open-label, 2-period, nonrandomized, phase-I, pharmacokinetic interaction design was used. Twelve healthy volunteers received a single oral dose of ivabradine (10 mg) followed by H perforatum (300 mg orally, 3 times a day) for 14 days, combining the last dose with another single dose of ivabradine. Pharmacokinetic data for ivabradine (S16257 [GenBank] ) and its main active metabolite (S18982) prior to and after the administration of H perforatum were analyzed. After repeated administration of H perforatum, highest observed concentration in plasma (C_max) and area under the concentration-time curve (AUC) were significantly decreased for ivabradine (32.7 ± 16.6 vs 15.4 ± 7.0 ng/mL, P < .01; 114 ± 39.1 vs 43.7 ± 12.0 ng·h/mL, P < .01, respectively), and for S18982 (C_max, 6.8 ± 3.7 vs 5.1 ± 2.0 ng/mL, P < .05; AUC, 56.2 ± 23.4 vs 38.3 ± 25.1 ng·h/mL, P < .01). Tendencies toward shorter time to C_max and lower apparent terminal half-life values were found. Pharmacokinetic results are consistent with an induction of ivabradine metabolism by H perforatum.

Key Words: Pharmacokinetics • interaction • ivabradine • Hypericum perforatum • induction • healthy volunteers • clinical trial

Address for reprints: A. Portolés, MD, PhD, Clinical Pharmacology Studies Unit, Clinical Pharmacology Service, Hospital Clínico San Carlos, c/Prof. Martín Lagos s/n, 28040 Madrid, Spain; e-mail: aportoles.hcsc{at}salud.madrid.org.

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