K. Vučićević (1), M. Jovanović (1), B. Golubović (1), S. Vezmar Kovačević (1), M. Prostran (2), Ž. Martinović (3), B. Miljković (1)
(1) Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia; (2) Department of Pharmacology, Clinical Pharmacology and Toxicology, University of Belgrade - School of Medicine, Belgrade, Serbia; (3) Institute of Mental Health, Department of Epilepsy and Clinical Neurophysiology, University of Belgrade - School of Medicine, Belgrade, Serbia
Objectives: The aim of the study was to explore impact of valproic acid (VPA) daily dose on phenobarbital (PB) oral clearance (CL/F) in adult patients with epilepsy.
Methods: Data were collected from 136 adult epileptic patients during routine therapeutic drug monitoring. Patients administered PB either as monotherapy or in combination with other antiepileptic drugs. Daily doses of PB were in range from 25 – 300 mg and dosage regimens were once, twice or three times a day. Patients co-treated with VPA administered doses in range from 450 – 2000 mg. Nonlinear mixed effects modelling was performed for the pharmacokinetic (PK) analysis using NONMEM® software (version 7.2). A one-compartment model with first-order absorption and elimination was used as a structural model. The FOCEI was used for parameter estimation. Based on literature data volume of distribution and absorption rate constants were fixed at 0.6 l/kg and 3 h-1, respectively [1]. Evaluation of final model was performed by internal validation technique.
Results: An average daily dose of PB was 130.2 ± 58.37 mg, while 25% of patients were treated with VPA dose of 1109 ± 433.9 mg/day. The interindividual variability was evaluated by an exponential model while residual variability was best described by proportional model. The estimate of CL/F for a typical patient was 0.291 l/h in the final model. PB CL/F was significantly influenced by VPA daily dose and correlation was best described by linear model. Concomitant treatment with usual VPA dose of 1000 mg/day resulted in PB CL/F average decrease of 20%. The stability of the model was confirmed by bootstrap resampling technique. The predictive performance was evaluated by adequate plots and indicated acceptable precision.
Conclusions: The final population PK model describes and quantifies influence of VPA daily dose on PB elimination. The results can be used for estimation of PB CL/F and individualization of PB dosing regimen, especially useful for patients co-treated with VPA.
References:
[1] Johannessen Landmark C, Johannessen SI, Tomson T. Host factors affecting antiepileptic drug delivery-pharmacokinetic variability. Adv Drug Deliv Rev. 2012;64(10):896-910.
Reference: PAGE 23 () Abstr 3058 [www.page-meeting.org/?abstract=3058]
Poster: Drug/Disease modeling - CNS