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

Abstract

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.

Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem

“…In contrast to several recent reports documenting substantial increases in verapamil half-life (Freedman et al 1981;Schwartz et al 1982bSchwartz et al , 1985Shand et al 1981), no increase in elimination half-life was observed by Eichelbaum and Somogyi (1984b) during long term dosing. Substantial inter-and intraindividual variations in morning trough and Anderson et al (1982) 3.43 ± 0.54 Freedman et al (1981) 5.04 ± 2.95 Wagner et al (1982) 9.17 ± 2.98 Somogyi et al (1981) Mooy et al (1985) Abbreviations: Cma• = maximum plasma concentration; tm8• = time of occurrence of Cma. ; CL" = apparent oral clearance; F = bioavailability; SVT = supraventricular tachyarrhythmias.…”

Short-Term Effect of Atrial Fibrillation on Atrial Contractile Function in Humans

“…An infusion of 0.005 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 verapamil was started 3 minutes later and continued until the protocol was completed. [11][12][13][14] The mean total verapamil dosage was 16.4Ϯ2.8 mg administered over 27.4Ϯ3.5 minutes. In these 6 patients, the post-AF sinus cycle length (785Ϯ109 ms) and atrial-His interval (96Ϯ27 ms) were the same as or longer than before verapamil (sinus cycle length, 735Ϯ79 ms, Pϭ0.10; atrial-His interval, 87Ϯ15 ms, Pϭ0.02).…”

Comparison of nonlinear pharmacokinetic parameters estimated from the sinusoidal perfusion and venous equilibrium models

“…Equation (19) indicates that a plot of 1nF versus R will yield a straight line with intercept equal to -V Y K Z corresponding to R = 0, and F = 1 or In F = 0 when R = VZ. Figure 1 presents such a plot based on the verapamil parameter values in Table 1.…”

“…Once values of V:, KZ, and Q are estimated for a given drug in a given subject one can construct a plot showing the dependency of systemic availability on dose rate using equation (19) based on the sinusoidal perfusion model. Equation (19) indicates that a plot of 1nF versus R will yield a straight line with intercept equal to -V Y K Z corresponding to R = 0, and F = 1 or In F = 0 when R = VZ. Figure 1 presents such a plot based on the verapamil parameter values in Table 1.…”