Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Validation of Individual Non-Linear Predictive Pharmacokinetic Parameters in a Rabbit Phenytoin Model

Kosta J Popović¹ , Mihalj Posa¹, Dusica J Popović², Dusan Lalosević³, Jovan K Popović²

¹Department of Pharmacy; ²Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine; ³Department of Veterinary Medicine, Faculty of Agriculture, University of Novi Sad, Novi Sad, Republic of Serbia.

For correspondence:- Kosta Popović Email: jovapop@neobee.net

Received: 24 February 2014 Accepted: 28 June 2014 Published: 18 August 2014

Citation: Popović KJ, Posa M, Popović DJ, Lalosević D, Popović JK. Validation of Individual Non-Linear Predictive Pharmacokinetic Parameters in a Rabbit Phenytoin Model. Trop J Pharm Res 2014; 13(8):1295-1302 doi: 10.4314/tjpr.v13i8.14

© 2014 The authors.
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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 (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.

Keywords: Phenytoin, Rabbit, Pharmacokinetic model, Multiple dosing, Non-linear, Individualization