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 twocompartmental 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. Formultiple 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.Keywords: Phenytoin, Rabbit, Pharmacokinetic model, Multiple dosing, Non-linear, Individualization
Highlights
Available studies on the pharmacokinetics of phenytoin in dogs [1], mice [2], rats [3] and humans [4] given different single doses have shown that in these species elimination of phenytoin from plasma is dependent on the dose and is non-linear
In the present study on rabbits using phenytoin as probe, we examined the impact of non-linear kinetic model on individual dose determination for specified therapeutic drug concentration
Some of the curves obtained with the large single doses (Figs 2 and 3) are not decreasing, which is expected for non-linear kinetics
Summary
Available studies on the pharmacokinetics of phenytoin in dogs [1], mice [2], rats [3] and humans [4] given different single doses have shown that in these species elimination of phenytoin from plasma is dependent on the dose and is non-linear. We have not found such a study performed on rabbits. Other reasons for using rabbits in the present work are as follows. Rabbits are ideal for pharmacokinetic studies, since higher animals like monkeys, which were commonly used in the past for pharmacokinetic research, are very expensive and demanding in terms of fostering and hosting [5]. Rabbits have been used extensively for such studies and show good sensitivity. Rabbits are more suitable for multiple sampling, which is required for pharmacokinetics
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