Validation of individual non-linear predictive pharmacokinetic parameters in a rabbit phenytoin model

Abstract

Purpose: To evaluate the predictive performance of phenytoin multiple dosing non-linear pharmacokinetic model in rabbits for possible application in therapy individualization in humans. Methods: Phenytoin was intravenously administered to 10 rabbits (2 - 3 kg). Plasma concentrations were measured by high pressure liquid chromatography (HPLC). Rabbits received 3 single phenytoin doses (11, 22 and 44 mg/kg) and plasma concentrations were fitted according to linear two-compartmental model. In all the rabbits, based on 3 different multiple doses (D1, D2, D3, range 9 - 15 mg/kg), 3 steady state plasma concentrations (Css1, Css2, Css3, range 20 - 56mg/l) were achieved. For multiple dosage, the non-linear parameters, Km and Vm, were calculated according to the equations: Km = (D1-D2)/[(D2/Css2)-(D1/Css1)] and Vm = D2+KmD2/Css2, and individually used to calculate Css3 = D3Km/(Vm-D3). Predicted and measured Css3 values were compared. Results: The values for pharmacokinetic parameters after single doses were dose-dependent. The pronounced inter-individual variations in Km (extreme values 18 - 91 mg/l differed 5.5 times) and Vm (11 - 28 mg/kg/h) values were recorded. Significant correlation of predicted Css3 with the measured value for the same dose (D3) was found (r = 0.854, N = 10, p < 0.01). There was no statistical difference between predicted and measured concentrations (t-dependent test = 1.074, p < 0.05). Conclusion: Non-linear parameters, Km and Vm, obtained from only two steady-state concentration measurements can be successfully used to compute and achieve a particular steady-state plasma concentration and optimal dosage regimen. © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved.