What are the plasma concentrations and interpatient variability of verapamil and norverapamil during long-term therapy in patients with hypertrophic obstructive cardiomyopathy?
Long-term verapamil therapy in hypertrophic obstructive cardiomyopathy patients exhibits massive interpatient variability in plasma concentrations, suggesting therapeutic drug monitoring may be necessary to guide dosing.
Plasma concentrations of verapamil and norverapamil were measured with a gas chromatographic method in 31 patients with hypertrophic obstructive cardiomyopathy during long-term maintenance therapy (6 months-5 years) with verapamil. In 20 patients on a maintenance dosage of 480 mg/day, verapamil concentrations approximately 12 hr after the last regular dose were 91 ± 76 ng/ml (mean ± SD) and levels 1 hr after an oral test dose of 160 mg were 355 ± 253 ng/ml. The values before and after the test dose were highly correlated, r = 0.7272 (p < 0.001). The concentration of norverapamil before the test dose in these 20 patients (160 ± 121 ng/ml) showed a strong positive correlation with the corresponding verapamil concentrations. Verapamil and norverapamil did not accumulate in plasma during long-term treatment with 480 mg daily. A 25-fold difference between patients on this dosage was found for verapamil plasma concentrations before the test dose and a 13-fold difference after it. This large interpatient variation may be mainly due to differences in the first-pass metabolism of verapamil. We recommend that verapamil plasma concentrations be measured to guide therapy with this drug.
Woodcock et al. (Tue,) studied this question.