Mibefradil pharmacokinetic and pharmacodynamic population analysis.
Mibefradil is a new T-channel selective calcium antagonist effective in the treatment of hypertension and chronic stable angina pectoris. In this study steady-state plasma mibefradil concentrations and pharmacodynamic measurements were obtained from American and European clinical studies and analyzed using NONMEM. Doses ranged from 12.5-200 mg orally once-daily. A linear one-compartment pharmacokinetic model with first-order absorption was employed. Best parameter estimates were as follows: absorption rate-constant = 2.7 hours-1, clearance = 5.7 L/hour, volume of distribution = 179 L. The bioavailability of the 25 mg oral dose relative to higher doses was 0.83. Conclusions based on the Emax model equations were that at average plasma concentrations achieved clinically (approximately 300 ng/ml and approximately 600 ng/ml for 50 and 100 mg/day, respectively) the effect on heart rate is near maximum, the effect on blood pressure is about 50% of maximum, and the effect on PQ interval is small. The model also predicts that diastolic blood pressure and heart rate reductions will tend to be greater in patients with higher baseline values and with increasing mibefradil plasma concentrations. The increase in PQ interval is strongly related to plasma mibefradil concentration. The population analysis shows that mibefradil pharmacokinetics and pharmacodynamics were not affected in a clinically relevant manner by demographic characteristics.
F. Hoffmann-La Roche, Basel, Switzerland.
H A
HA
Welker
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L
Banken
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D020748:Mibefradil; D008875:Middle Aged; D012737:Sex Factors; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil