Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients

Abstract

Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg⁻¹, and the steady-state volume of distribution (V_ss) was 2.16 1·kg⁻¹. The distribution (t_1/2α) and elimination (t_1/2β) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min⁻¹·kg⁻¹. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CV_intra) as it was between patients (CV_inter). The steady-state trough plasma concentration (C_min obs) ranged from 4.8 to 30 mg·1⁻¹ (mean 16.0 mg·1⁻¹ and median 14.3 mg·1⁻¹). Peak concentrations (C_max obs) ranged from 8.35 to 45 mg·1⁻¹ (25.4 mg·1⁻¹, and median 23.3 mg·1⁻¹). The values of V1 and V_ss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg⁻¹. The mean V_ss was 2.68 1·kg⁻¹, with a CV_intra of 12.6 to 56% and a CV_inter of 13.2%. A shorter distribution half-life t_1/2α was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t_1/2β and the mean residence time became longer due to a decrease in clearance. For t_1/2β the mean value was 16.3 h. The mean MRT was 21.9 h, CV_intra 9.19 to 48.5%, and the CV_inter 35.3%. The mean clearance was 2.16 ml·min⁻¹·kg⁻¹, CV_intra 7.28 to 25.5%, and the CV_inter 20.4%. This value is 50% lower than after a single dose.

Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.