<abstract xmlns="http://www.w3.org/1999/xhtml"><p>The aim of the present study was to investigate the distribution of <italic>CYP2C8</italic> variants <italic>*3</italic> and <italic>*5</italic>, as well as their effect on carbamazepine pharmacokinetic properties, in 40 epileptic pediatric patients on carbamazepine treatment. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and allele-specific (AS)-PCR methods, and steady-state carbamazepine plasma concentrations were determined by high performance liquid chromatography (HPLC). The <italic>CYP2C8 *3</italic> and <italic>*5</italic> polymorphisms were found at frequencies of 17.5 and 0.0%, respectively. After dose adjustment, there was a difference in daily dose in <italic>CYP2C8*3</italic> carriers compared to non carriers [mean ± standard deviation (SD): 14.19 ± 5.39 <italic>vs</italic>. 15.46 ± 4.35 mg/kg; <italic>p</italic> = 0.5]. Dose-normalized serum concentration of carbamazepine was higher in <italic>CYP2C8*3</italic> (mean ± SD: 0.54 ± 0.18 vs. 0.43 ± 0.11 mg/mL, <italic>p</italic> = 0.04), and the observed correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in <italic>CYP2C8*3</italic> non carriers (r = 0.52, <italic>p</italic> = 0.002). However, the population pharmacokinetic analysis failed to demonstrate any significant effect of <italic>CYP2C8 *3</italic> polymorphism on carbamazepine clearance [CL L/h = 0.215 + 0.0696*SEX+ 0.000183*DD]. The results indicated that the <italic>CYP2C8*3</italic> polymorphism might not be of clinical importance for epilepsy treatment in pediatric populations.</p></abstract>

The aim of the present study was to investigate the distribution of CYP2C8 variants *3 and *5, as well as their effect on carbamazepine pharmacokinetic properties, in 40 epileptic pediatric patients on carbamazepine treatment. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and allele-specific (AS)-PCR methods, and steady-state carbamazepine plasma concentrations were determined by high performance liquid chromatography (HPLC). The CYP2C8 *3 and *5 polymorphisms were found at frequencies of 17.5 and 0.0%, respectively. After dose adjustment, there was a difference in daily dose in CYP2C8*3 carriers compared to non carriers [mean ± standard deviation (SD): 14.19 ± 5.39 vs. 15.46 ± 4.35 mg/kg; p = 0.5]. Dose-normalized serum concentration of carbamazepine was higher in CYP2C8*3 (mean ± SD: 0.54 ± 0.18 vs. 0.43 ± 0.11 mg/mL, p = 0.04), and the observed correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in CYP2C8*3 non carriers (r = 0.52, p = 0.002). However, the population pharmacokinetic analysis failed to demonstrate any significant effect of CYP2C8 *3 polymorphism on carbamazepine clearance [CL L/h = 0.215 + 0.0696*SEX+ 0.000183*DD]. The results indicated that the CYP2C8*3 polymorphism might not be of clinical importance for epilepsy treatment in pediatric populations.

The influence of <italic>CYP2C8*3</italic> on carbamazepine serum concentration in epileptic pediatric patients

Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac,

Department of Pediatrics, Faculty of Medical Sciences, University of Kragujevac,

Department of Surgery, Faculty of Medical Sciences, University of Kragujevac,

Balkan Journal of Medical Genetics

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The influence of  on carbamazepine serum concentration in epileptic pediatric patients

The aim of the present study was to investigate the distribution of CYP2C8 variants *3 and *5, as well as their effect on carbamazepine pharmacokinetic...

	Observed Frequency	95% CI
Nucleotide change:416G>A475delA	0.100 (8/80)0.000 (0/80)	0.050, 0.1880.000, 0.056
Haplotype:CYP2C81ACYP2C83CYP2C8*5	0.900 (72/80)0.100 (8/80)0.000 (0/80)	0.812, 0.9500.050, 0.1880.000, 0.056
Genotype:CYP2C81A/1ACYP2C81A/3CYP2C83/*3	0.825 (33/40)0.150 (6/40)0.025 (1/40)	0.676, 0.8610.068, 0.2450.000, 0.109

Parameters	NONMEM		Bootstrap Analysis
	Estimate	95% CIa Estimate ± 1.96 × (standard error of the estimate).	Estimate	95% CIb Percentile (2.5 and 97.5) of the ranked bootstrap parameter estimates.
Clearance (L/h)	0.215	0.176-0.254	0.207	0.189-0.225
Sex	0.0696	0.0545-0.0847	0.0698	0.0527-0.869
Daily dose of carbamazepine (mg/L)	0.000183	0.000079-0.000287	0.000194	0.000141-0.000247
Inter-individual variance of CL	0.0626	0.0371-0.0881	0.0669	0.058-0.0758
Residual variance (exponential)	0.0249	0.018-0.318	0.0262	0.023-0.0294

The influence of CYP2C8*3 on carbamazepine serum concentration in epileptic pediatric patients

Article Category: Original Article

Published Online: Aug 02, 2016

Page range: 21 - 28

DOI: https://doi.org/10.1515/bjmg-2016-0003

Keywords
Carbamazepine pharmacokinetics, Children, Population pharmacokinetics

© 2016 Walter de Gruyter GmbH, Berlin/Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleotide change, haplotype and genotype frequencies of CYP2C8 in Serbian epileptic pediatric patients on carbamazepine treatment.

The final model parameter estimates.

The influence of CYP2C8*3 on carbamazepine serum concentration in epileptic pediatric patients

Article Category: Original Article

Published Online: Aug 02, 2016

Page range: 21 - 28

DOI: https://doi.org/10.1515/bjmg-2016-0003

KeywordsCarbamazepine pharmacokinetics, Children, Population pharmacokinetics

© 2016 Walter de Gruyter GmbH, Berlin/Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleotide change, haplotype and genotype frequencies of CYP2C8 in Serbian epileptic pediatric patients on carbamazepine treatment.

The final model parameter estimates.

Keywords
Carbamazepine pharmacokinetics, Children, Population pharmacokinetics