No clinically relevant CYP3A induction with the dual angiotensin-converting enzyme/neutral endopeptidase inhibitor, M100240.
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 microM, at 1 microM-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 EC(50) approximately 1.5 microM. 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(0-24 h) 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.
Martin
Nancy E
NE
Drug Metabolism and Pharmacokinetics, Aventis Pharmaceuticals, Inc., 1041 Route 202-206, P.O. Box 6800, Mailstop M303B, Bridgewater, NJ 08807-0800, USA.
Howell
Stanley R
SR
Martin
Louis L
LL
Cirillo
Iolanda
I
Barrett
Jeffrey S
JS
D000293:Adolescent; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001552:Benzazepines / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D011725:Pyridines / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D011725:Pyridines; C085683:MDL 100240; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D015260:Neprilysin; D008874:Midazolam