Effect of CYP2C9/CYP2C19 polymorphisms of pharmacokinetics of phenobarbital in Korean neonatal seizure patients

Abstract

Phenobarbital, 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 phenobarbital metabolism was affected by cytochrome P450 (CYP) 2C9/2C19 polymorphisms in adults requiring dose adjustment. The aim of the study was to evaluate the effects of CYP 2C9/2C19 genetic polymorphisms on phenobarbital pharmacokinetics (PK) in neonates and infants with seizures.CYP2C9/CYP2C19 (homozygous extensive metabolizer; wild type: CYP2C91*1/*1, CYP2C19*1/*1, heterozygous extensive metabolizer: CYP2C19*1/*2, *1/*3 and poor metabolizer: CYP2C9*1/*3, CYP2C19*2/*2, *2/*3) genetic polymorphisms in 52 neonates and infants with seizures, who were hospitalized for treatment at Gangnam Severance Hospital and Severance Children’s Hospital, were analyzed. PK parameters were compared based on genotypes. The NONMEM program was used for population PK modeling. No significant differences in phenobarbital clearance (CL), volume of distribution (Vd) and concentrations were shown among the CYP2C9/2C19 genotype groups. The results of PK modeling were as follows: Vd=3590 * (body weight (BWT)/4)0.766 * (AGE/2)0.283 and CL=32.6*(BWT/4)1.21.Phenobarbital PK parameters of neonates and infants with seizures were not significantly different among the groups with different CYP2C9/CYP2C19 genotypes. The addition of CYP2C9/CYP2C19 genotypes to PK models did not improve the dosing strategies in neonates and infants.