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No Clinically Relevant CYP3A Induction with the Dual Angiotensin-Converting Enzyme/Neutral Endopeptidase Inhibitor, M100240

From Drug Metabolism and Pharmacokinetics, Aventis Pharmaceuticals Inc., Bridgewater, New Jersey.

M100240, an acetate thioester of MDL 100,173, is a dual angiotensin-converting enzyme/neutral endopeptidase inhibitor currently in Phase II development. M100240 and MDL 100,173 were evaluated in an in vitro cytochrome P450 human hepatocyte model for enzyme induction. Although a dose-dependent CYP3A induction was observed between 10 and 100 µM, at 1 µM—which approaches clinically relevant plasma concentrations in humans—there was no evidence of CYP3A induction. An in vitro reporter gene assay also demonstrated the CYP3A isozyme induction potential of M100240 and MDL 100,173 with an EC₅₀ 1.5 µM. The present study evaluated the potential for CYP3A enzyme induction in healthy volunteers. In an open-label, single-sequence, replicate-design study using midazolam as a CYP3A probe in 13 healthy volunteers, we found no evidence of clinically relevant CYP3A induction after multiple-dose administration of 50 mg M100240 orally once daily for 15 days. Single and multiple doses of M100240 increased the midazolam AUC_0-24h about 1.6-fold compared to baseline, suggesting weak CYP3A inhibition. Concomitant administration of midazolam and M100240 was generally safe and well tolerated. Although in vitro CYP3A induction at exposures in excess of clinically relevant human plasma concentrations has been demonstrated, there is no clinical evidence of CYP3A induction with M100240 administration at proposed therapeutic doses.

Key Words: M100240 • ACE/NEP inhibitor • CYP3A induction • drug-drug interactions • midazolam • pharmacokinetics

Address for reprints: Nancy E. Martin, PharmD, FCP, Drug Metabolism and Pharmacokinetics, Aventis Pharmaceuticals, Inc., 1041 Route 202-206, P.O. Box 6800, Mailstop M303B, Bridgewater, NJ 08807-0800.

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