Related Experiment Videos
Mibefradil pharmacokinetic and pharmacodynamic population analysis
1F. Hoffmann-La Roche, Basel, Switzerland.
International Journal of Clinical Pharmacology Research
|July 24, 1998
Summary
Mibefradil effectively treats hypertension and angina by reaching near-maximum heart rate reduction and 50% blood pressure reduction at clinical plasma concentrations. Its effects are concentration-dependent and not significantly impacted by patient demographics.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Cardiovascular Medicine
Background:
- Mibefradil is a T-channel selective calcium antagonist.
- It is effective for hypertension and chronic stable angina pectoris.
Purpose of the Study:
- To analyze steady-state plasma mibefradil concentrations and pharmacodynamic measurements.
- To develop a pharmacokinetic model for mibefradil.
Main Methods:
- Analysis of data from American and European clinical studies using NONMEM.
- Application of a linear one-compartment pharmacokinetic model with first-order absorption.
- Utilized Emax model equations for pharmacodynamic analysis.
Main Results:
- Key pharmacokinetic parameters: absorption rate-constant (2.7 hr-1), clearance (5.7 L/hr), volume of distribution (179 L).
- Bioavailability of 25 mg dose was 0.83 relative to higher doses.
- Clinical concentrations yield near-maximum heart rate effect, ~50% maximum blood pressure effect, and small PQ interval effect.
Conclusions:
- Mibefradil's cardiovascular effects are concentration-dependent.
- Higher baseline values and increasing concentrations correlate with greater blood pressure and heart rate reduction.
- Demographic factors did not clinically relevantly affect mibefradil pharmacokinetics or pharmacodynamics.