Balkan Journal of Medical Genetics

THE INFLUENCE OF CYP2C8*3 ON CARBAMAZEPINE SERUM CONCENTRATION IN EPILEPTIC PEDIATRIC PATIENTS
Milovanovic DD, Milovanovic JR, Radovanovic M, Radosavljevic I, Obradovic S, Jankovic S, Milovanovic D, Djordjevic N
*Corresponding Author: M.D., Ph.D., Associate Professor, Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000 Kragujevac, Serbia. Tel: +381-34-306-800, ext 223. Fax: +381-34-306-800. E-mail: natashadj2002@yahoo.com
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RESULTS

The assessment included 24 male and 16 female pediatric patients, aged 4-16 years (median: 11 years), weighing 17 to 65 kg (median: 39 kg). All patients received daily doses of 260 to 1000 mg orally as tablets or syrup, and four of them were on concomitant therapy with valproate. Observed CYP2C8 genotype frequencies (Table 1) were in accordance with the Hardy-Weinberg equilibrium (χ2 <1.111, p = 0.05). As there was only one carrier of the CYP2C8*3/*3 genotype (no CYP2C8*5 was observed), all subjects were designated as either CYP2C8*3 carriers (CYP2C8*1A/*3 or CYP2C8*3/*3) or CYP2C8*3 non carriers (CYP2C8*1A/*1A). After dose adjustment based on the serum concentration, the daily carbamazepine dose was found to be lower in CYP2C8*3 carriers compared to CYP2C8*3 non carriers, although the difference was not statistically significant [mean ± SD (standard deviation): 14.19 ± 5.39 mg/kg vs. 15.46 ± 4.35 mg/kg, p = 0.5]. The observed dose and p values remained exactly the same when valproate users were excluded from comparison. At the same time, higher dose-normalized serum concentration of carbamazepine was observed in CYP2C8*3 carriers compared to CYP2C8 *3 non carriers (mean ± SD: 0.54 ± 0.18 vs. 0.43 ± 0.11 mg/mL, p = 0.04) (Figure 1). The observed correlation between weightadjusted carbamazepine dose and carba-mazepine concentration after dose adjustment was significant only in CYP2C8*3 non carriers (r = 0.52, p = 0.002) (Figure 2). The mean population value for carbamazepine clearance, estimated by the base population pharmacokinetics model, was 4.04 L/h. Inter- and intrapatient variability was best described by exponential model error, with the values of 41.37 and 22.64%, respectively. Out of six examined factors, only three met the minimum objective function value (MOF) difference requirement, and thus, were included in the full model: the total carbamazepine daily dose, sex and concomitant therapy with valproate. The process of backward deletion of covariates from the full model resulted in the following equation: CL (L/h)=0.215+0.0696*SEX+0.000183*DD, where SEX has a value of 1 if male and 0 if female, and DD is the total carbamazepine daily dose (mg/day). Value of MOF in the final model was 148.759 units lower compared to the base model. The final model parameter estimates are presented in Table 2. Both inter- and intra-patient variability were decreased by 25.42 and 15.88%, respectively. The bootstrapping analysis that was conducted on 200 replicated data with replacement, resulted in similar values of carbamazepine clearance, effects of total carbamazepine daily dose, sex, and inter- and intrapatients variability, indicating a good precision and stability of the final model.

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