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 (C_ss1, C_ss2, C_ss3, range 20 - 56mg/l) were achieved. For multiple dosage, the non-linear parameters, K_m and V_m, were calculated according to the equations: K_m = (D₁-D₂)/[(D₂/C_ss2)-(D₁/C_ss1)] and V_m = D₂+K_mD₂/C_ss2, and individually used to calculate C_ss3 = D₃K_m/(V_m-D₃). Predicted and measured C_ss3 values were compared.

Results: The values for pharmacokinetic parameters after single doses were dose-dependent. The pronounced inter-individual variations in K_m (extreme values 18 – 91 mg/l differed 5.5 times) and V_m (11 – 28 mg/kg/h) values were recorded. Significant correlation of predicted C_ss3 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, K_m and V_m, 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.