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

Area of Science:

• Pharmacology
• Cardiovascular Medicine
• Drug Development

Background:

• Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) is a therapeutic strategy for hypertension, heart failure, and renoprotection.
• M100240, a dual ACE/NEP inhibitor, has been investigated for hypertension management.

Purpose of the Study:

• To characterize the relationship between M100240 exposure and neurohormonal response.
• To optimize M100240 dosing for future clinical studies in hypertension.

Main Methods:

• A model-based analysis using NONMEM was performed on data from 62 healthy subjects and 189 hypertensive patients.
• Pharmacokinetic-biomarker and blood pressure response models were fitted to data from once-daily oral M100240 doses (2.5-50 mg).

Main Results:

• An Emax model adequately described the concentration-dependent inhibition of ACE activity by MDL100,173.
• No clear dose- or concentration-dependent responses were observed for NEP inhibition or blood pressure.
• Simulations indicated that 50 mg M100240 once daily achieved target 90% ACE inhibition in only 20% of subjects after 24 hours.

Conclusions:

• Once-daily oral M100240 up to 50 mg demonstrated insufficient ACE and NEP inhibition for significant blood pressure lowering.
• Higher doses (e.g., 25 mg TID or 50 mg BID) are likely required to achieve target ACE inhibition in at least 50% of patients over 24 hours.
• Divided dosing regimens may enhance ACE inhibition and therapeutic efficacy.