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DRUG METABOLISM

Influence of Azimilide on CYP2C19-Mediated Metabolism

Mohamed El Mouelhi, MD, PhD, Dan J. Worley, BS, Barbara Kuzmak, PhD, Anthony J. Destefano, PhD and Gary A. Thompson, PhD

From Procter & Gamble Pharmaceuticals, Mason, Ohio.

The purpose of this study was to assess the influence of multiple-dose oral administration of azimilide dihydrochloride on CYP2C19-mediated metabolism. A two-period, randomized crossover study was conducted in 40 healthy male subjects who were phenotyped as extensive CYP2C19 metabolizers. Oral doses of placebo or 125 mg of azimilide dihydrochloride were administered every 12 hours for 3 days, followed by every 24 hours for 5 days; 20 mg omeprazole was coadministered on Day 8. Blood or plasma samples were obtained over 24 hours and analyzed for azimilide or omeprazole/5-hydroxyomeprazole using high-performance liquid chromatography with tandem mass spectrometry. Data were analyzed using "noncompartmental" analysis. Azimilide blood concentrations observed in this study were similar to those previously observed at steady state in patients. Based on AUCm/AUCp for omeprazole, azimilide does not significantly inhibit CYP2C19-mediated metabolism (90% confidence interval [CI] = 104%-111%). For 5-hydroxyomeprazole, no significant changes in pharmacokinetics were observed. For omeprazole, a statistically significant decrease (~12%) was observed for AUC. However, this change was small and is not expected to be clinically important since the CI was contained within those used to establish bioequivalence. These results indicate that azimilide does not inhibit CYP2C19-mediated metabolism. Since this isozyme had the lowest in vitro IC50 values for the cytochrome P450s most commonly involved with the metabolism of drugs (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), azimilide-related drug interactions mediated via these isozymes are not anticipated.

Key Words: Azimilide • pharmacokinetics • drug interactions • CYP 2C19 • omeprazole

Address for reprints: Gary A. Thompson, PhD, Clinical Pharmacology and Pharmacokinetics, Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, OH 45040-9462.


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