Prediction of steady-state verapamil plasma concentrations in children and adults

With data on adults from two previous articles it was found that the average steady-state plasma concentration of verapamil in subjects on long-term oral therapy of 80 mg every 6 hr (Y) correlated strongly with the area under the curve from zero to infinity (AUC0-x/6 (X) where the area refers to that for a single oral dose of 80 mg (Y - 2.41X, n - 15, r - 0.923, P less than 0.001). Steady-state concentrations are predictable from the single-dose data, with an average absolute deviation of 11.1%. We gave seven children (7 to 19 yr old) an initial intravenous bolus dose of 0.1 mg/kg, followed by a 20-min constant rate infusion of 0.007 mg/kg/min. Twenty-four hours after the bolus dose they were put on oral therapy (40 to 80 mg every 6 hr) and 1 mo later the minimum steady-state verapamil plasma concentration (Cminss) was measured. Plasma concentration-time data obtained after the infusion were fitted to biexponential (two sets) or triexponential equations (five sets). The coefficients of the postinfusion polyexponential equations were converted to those for the 0.1-mg/kg bolus dose alone. Mean parameters estimated were: plasma clearance 0.500 l/min, steady-state volume of distribution 279 l, V beta 394 l, half-life 9.17 hr, and mean residence time 10.0 hr. Many correlations were made between the oral Cminss values and functions obtained from the intravenous data. The best correlation was that between Cminss and the predicted steady-state concentration at 3 hr after dosing when bolus doses would be given at 6-hr intervals based on the single-dose intravenous date (r = 0.985, P less than 0.001); this correlation allowed Cminss to be predicted with an average absolute deviation of 10%. Norverapamil was measured in plasma after oral dosing, but was not detectable after intravenous dosing.