Validation of Individual Non-Linear Predictive Pharmacokinetic Parameters in a Rabbit Phenytoin Model|
Popović, Kosta J.; Poša, Mihalj; Popović, Dušica J.; Lalošević, Dušan & Popović, Jovan K.
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.
Phenytoin; Rabbit; Pharmacokinetic model; Multiple dosing; Non-linear; Individualization