VERAPAMIL AND NORVERAPAMIL PLASMA-LEVELS IN INFANTS AND CHILDREN DURING CHRONIC ORAL TREATMENT

Verapamil and norverapamil trough plasma levels were measured in 22 children, aged from 15 days to 17 years, under chronic oral treatment with the drug (mean daily dose +/- SD: 4.9 +/- 1.4 mg/kg) for supraventricular tachyarrhythmias (n = 20) or hypertrophic cardiomyopathy (n = 2). Overall, 67 determinations were available(1 to 11 per patient) and the mean concentration values (+/- SD) were 43.3 +/- 36.4 ng/ml for verapamil and 41.7 +/- 28.9 ng/ml for norverapamil. Verapamil and norverapamil trough concentrations were correlated with the daily dose (p < 0.05) but a wide intersubject variability was present at any given dose and the regression line did not pass through the origin of axes (x-axis intercept: 1.2 mg/kg for verapamil, 0.9 mg/kg for norverapamil). To study the influence of age on drug kinetics, verapamil plasma concentrations corrected by daily dose/kg ([V]/D) and norverapamil to verapamil concentration ratios (N/V) (taken as an index of metabolic clearance) were divided according to age quartiles. The median [V]/D was higher in the first and in the fourth age quartile than in the other two age groups. On the contrary, median N/V ratio increased with age, suggesting that drug metabolism was improving during the first year of life. Four children developed typical adverse reactions to the drug (bradycardia, AV block, hypotension). In one case verapamil plasma levels were definitely high (294 ng/ml). In the other three cases, concomitant factors (such as very young age and heart disease) seem to have contributed to drug toxicity.