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.
Reference: PAGE 18 (2009) Abstr 1489 [www.page-meeting.org/?abstract=1489]
Poster: Applications- CNS