Effect of Valproic Acid Daily Dose on its Clearance in Adult Patients with Epilepsy – Population analysis of TDM data
K. Vučićević(1), B. Miljković(1), M. Pokrajac (1), M. Prostran (2), Ž. Martinović (3), R. Veličković (4), I. Grabnar(5)
(1) Department of Pharmacokinetics, Faculty of Pharmacy, University of Belgrade, Serbia; (2) Department of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, University of Belgrade, Serbia; (3) School of Medicine, University of Belgrade, Institute of Mental Health, Department of Epilepsy and Clinical Neurophysiology, Belgrade, Serbia; (4) Institute of Mental Health, Belgrade, Serbia; (5) The Chair of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Slovenia.
Objectives: The aim of the study was to investigate the influence of valproic acid (VPA) daily dose on its oral clearance (CL/F) using therapeutic drug monitoring (TDM) data in adult patients with epilepsy.
Methods: A total of 200 measured total (bound + free) VPA concentrations were obtained from 129 adult patients. VPA was administered 1-3 times per day in the form of film tablets containing 333 mg of sodium VPA and 145 mg of VPA (Eftil® retard 500, Hemofarm, Serbia) either as monotherapy or in combination with other antiepileptic drugs. Nonlinear mixed effects modeling was applied for the pharmacokinetic (PK) analysis using NONMEM software (Version 6 level 2, GloboMax LLC, Ellicott City, MD, USA) and Perl speaks NONMEM (Version 2.3.0, http://psn.sourceforge.net). A one-compartment model with first-order absorption and first-order elimination as implemented in ADVAN2/TRANS2 PREDPP subroutine was used to fit the concentration-time data. Based on literature data volume of distribution and absorption rate constants were fixed at 0.14 L/kg and 0.67 h-1, respectively. Validation of the final model was performed.
Results: An average daily dose of VPA in the model building set was 1107.75 ± 412.05 mg/day, while in model validation set 1031.25 ± 306.74 mg/day. Interindividual variability of VPA CL/F was best described by the exponential error model, while a combination error model most adequately characterized residual variability in VPA concentrations. In the first step inclusion of VPA daily dose (DVPA) greater than 1000 mg/day into the base model, resulted in the highest decrease in objective function value (OFV) of 16.809 (p < 0.0001) and reduced interindividual variability. Estimates generated by NONMEM indicated that if VPA daily dose is greater than 1000mg/day, VPA CL/F increase by 43%. Interindividual variability of VPA CL/F (95% CI) was 31.9% (22.4 – 37.9%), while residual variability was 23.8% (15.4 – 32.4%) for the proportional and 13.2 mg/l (3.17 – 18.8 mg/L) for the additive component. Model validation indicated little bias, good precision and acceptable predictive performance.
Conclusions: In the present study, CL/F was found to increase significantly with DVPA greater than 1000 mg/day in a step-like manner. The relationship between DVPA and CL/F may be associated with the so-called TDM-effect. This implies the use of higher doses of VPA in patients with higher elimination rates, or in patients who are insensitive to lower VPA doses.
References:
Bondareva IB, Jelliffe RW, Sokolov AV, Tischenkova IF. Nonparametric population modeling of valproate pharmacokinetics in epileptic patients using routine serum monitoring data: implication for dosage. J Clin Pharm Ther 2004;29:105-20.
