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Optimizing Dose Selection with Modeling and Simulation: Application to the Vasopeptidase Inhibitor M100240
Author(s) -
Pfister Marc,
Martin Nancy E.,
Haskell Lloyd P.,
Barrett Jeffrey S.
Publication year - 2004
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270004265365
Subject(s) - ace inhibitor , medicine , blood pressure , pharmacology , angiotensin converting enzyme , nonmem , pharmacokinetics , benazepril
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.