Optimizing dose selection with modeling and simulation: Application to the vasopeptidase inhibitor M100240

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 doily 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.