Effects of cytochrome P450 (CYP)2C19 polymorphisms on pharmacokinetics of Phenobarbital in neonates and infants with seizures

Young-Mock Lee, Soon-Min Lee, Jae-Yong Chung, Min-Soo Park, Ran Namgung, Kook-In Park, Chul Lee. Yonsei University College of Medicine, Department of Pediatrics, Republic of Korea

Background: Phenobarbital (PB), commonly used as the preferred treatment for neonatal seizure, is a drug that requires careful dose adjustments based on therapeutic drug monitoring. It has been reported that PB metabolism was affected by cytochrome P450 (CYP)2C19 polymorphisms in adults requiring dose adjustment.

Aim: This study aimed to evaluate the effects of CYP2C19 genetic polymorphisms on PB pharmacokinetics (PK) in neonates and infants with seizures.

Methods CYP2C19 (wild type: CYP2C19*1/*1, heterozygous extensive metabolisers: CYP2C19*1/*2, *1/*3 and poor metabolisers: CYP2C19*2/*2, *2/*3) genetic polymorphisms in 52 neonates and infants with seizures were analysed. PK parameters were compared based on genotypes. The NONMEM program was used for population PK modelling.

Results: No significant difference in PB clearance (CL), volume of distribution (Vd) and concentrations were shown among the CYP2C19 genotype groups. The results of PK modelling were as follows: Vd=3590×(body weight (BWT)/4)0.766 ×(AGE/2)0.283 and CL=32.6×(BWT/4)1.21.

Conclusions: PB PK parameters of neonates and infants with seizures were not significantly different among the groups with different CYP2C19 genotypes. The addition of CYP2C19 genotyping to PK models did not improve the dosing strategies in neonates and infants.