title: Optimizing dose selection with modeling and simulation: application to the vasopeptidase inhibitor M100240.
abstract: Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) has gained increasing interest in the treatment of hypertension, heart failure, and renoprotection. Specifically, M100240, the thioester of the dual ACE/NEP inhibitor MDL100,173, has been evaluated in the management of hypertension. A model-based analysis, including simulations, was employed to characterize the relationship between individual M100240 drug exposure and neurohormonal response and to optimize the dose selection for future clinical studies. Sixty-two healthy subjects and 189 hypertensive patients were studied after oral once-daily administration of 2.5, 5, 10, 25, or 50 mg M100240. Pharmacokinetic-biomarker and blood pressure response models were fitted to the data with the computer program NONMEM. A direct inhibitory E(max) model adequately described the relationship between MDL100,173 concentration and ACE activity. No clear concentration or dose-dependent NEP or blood pressure responses were evident. Given a target 90% ACE inhibition, simulation reveals that (1). 50 mg M100240 once daily produces adequate ACE inhibition 24 hours postdose in only 20% of subjects, and (2). higher and/or more frequent doses on the order of 25 mg three times daily or 50 mg twice daily are required to achieve the target ACE inhibition in at least 50% of patients over 24 hours. Insufficient blood pressure-lowering effects were observed in healthy subjects and hypertensive patients due to inadequate ACE and NEP inhibition with once-daily oral doses of up to 50 mg of M100240. Divided doses might provide target ACE inhibition in more patients.
authors.affiliation: Aventis Pharmaceuticals, 1041 Route 202-206, Bridgewater, NJ 08807, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Pfister
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Martin
authors.forename: Lloyd P
authors.initials: LP
authors.lastname: Haskell
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001552:Benzazepines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D008954:Models, Biological; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D015415:Biomarkers; D011725:Pyridines; C085683:MDL 100240; D015260:Neprilysin