Population pharmacokinetic model of topiramate and its major metabolite in adult epileptic patients
M. Jovanovic (1), D. Sokic (2) I. Grabnar (3), T.Vovk (3), R. Roskar (3), D. Milosheska (3), M. Prostran (4), B. Golubovic (1), K. Vucicevic (1), B. Miljkovic (1)
(1) Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Serbia; (2) Clinic of Neurology, Clinical Centre of Serbia, Belgrade; (3) Department of Biopharmaceutics and Pharmacokinetics, University of Ljubljana - Faculty of Pharmacy, Slovenia; (4) Departmant of Pharmacology, Clinical Pharmacology and Toxicology, University of Belgrade - School of Medicine, Serbia.
Objectives: The aim of the study was to characterize metabolic profile of topiramate (TPM) and to assess influence of enzyme induction by carbamazepine (CBZ) on first-order rate constant of metabolite (2,3-O-des-isopropylidene TPM) formation.
Methods: Data were collected from 68 adult epileptic patients on mono- or co-therapy of TPM and other antiepileptic drugs. Daily doses of TPM were in range from 50-1200 mg and dosage regimens were once, twice or three times a day. Steady-state TPM and its metabolite concentrations were determined in blood samples (1-2 per patient) by liquid chromatography tandem mass spectrometry assay. The population pharmacokinetic (PK) analysis was performed using NONMEM® software (version 7.3) and Perl speaks NONMEM® (version 4.4.0). Parameters estimation was performed by FOCE with interaction. The influence of CBZ daily dose on first-order rate constant of metabolite formation was evaluated.
Results: Mean first-order rate constant of metabolite formation was estimated at 0.00444 h-1, while first-order rate constant of metabolite elimination was 0.0106 h-1. The interindividual variability was evaluated by an exponential model while residual variability was best described by proportional for parent and additive model for metabolite. Average daily dose of CBZ were 1010.5 ± 409.5 mg (range of 300-1600 mg). Daily dose of CBZ significantly (p < 0.05) increased parameter of elimination and interindividual variability was reduced. Among tested relations, influence of this covariate was best described by exponential model. Volume of distribution was fixed at 0.6 l/kg while first-order elimination rate constant was fixed at 0.038 h-1. Acceptable model performances were confirmed by adequate diagnostic plots and internal validation.
Conclusions: The final population PK model describes and quantifies influence of CBZ daily dose on first-order rate constant of metabolite formation. The results confirm that CBZ is inducer of TPM metabolism and importance of dosage regimen adjustment in routine patient care of patient co-treated with this drug.
References:
[1] Britzi M, Perucca E, Soback S, Levy RH, Fattore C, Crema F, Gatti G, Doose DR, Maryanoff BE, Bialer M. Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine. Epilepsia. 2005;46(3):378-84.