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: Marc Pfister, Nancy E Martin, Lloyd P Haskell, Jeffrey S Barrett
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 44 Issue 6 Pg. 621-31 (Jun 2004) ISSN: 0091-2700 [Print] England
• PMID: 15145970 (Publication Type: Clinical Trial, Comparative Study, Controlled Clinical Trial, Journal Article)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Benzazepines
• Biomarkers
• Pyridines
• MDL 100240
• Neprilysin

Topics

• Angiotensin-Converting Enzyme Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Benzazepines (administration & dosage, pharmacokinetics, pharmacology)
• Biomarkers (blood)
• Blood Pressure (drug effects)
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Humans
• Hypertension (drug therapy, metabolism)
• Models, Biological
• Neprilysin (antagonists & inhibitors)
• Pyridines (administration & dosage, pharmacokinetics, pharmacology)