Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.
OBJECTIVE
The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients.


METHODS
In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model.


RESULTS
According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F.


CONCLUSIONS
Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.
Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, 11000, Serbia, kacav@pharmacy.bg.ac.rs.
Katarina
K
Vučićević
Marija
M
Jovanović
Bojana
B
Golubović
Sandra Vezmar
SV
Kovačević
Branislava
B
Miljković
Žarko
Ž
Martinović
Milica
M
Prostran
D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010634:Phenobarbital / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077236:Topiramate; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D014635:Valproic Acid; D000077213:Lamotrigine; D010634:Phenobarbital