Abstract
AIMS: Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug. METHODS: Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment. Population pharmacokinetic-pharmacogenetic analysis of omeprazole and its metabolites was performed using NONMEM. RESULTS: Data fitted a one-compartment parent and metabolite model with first-order absorption and elimination. CYP2C19 and CYP3A4 are predominantly involved in the metabolism of omeprazole despite their relatively low activities compared to adults. The clearance of omeprazole converted to 5-hydroxy-omeprazole (CL(OMZ-M1) ) increases with postnatal age. In CYP2C19 poor and intermediate metabolizers, model-predicted CL(OMZ-M1) are 12.5% (5-95% percentile: 3-14.9%) and 44.9% (5-95% percentile: 29.9-72.6%) of the value in extensive/ultrarapid metabolizer, respectively. Model-predicted absorption rate constant of omeprazole is 6.93 (5-95% percentile: 3.01-14.61) times higher in ABCB1 homozygous mutant patients, 1.86 (5-95% percentile: 0.86-3.47) times higher in ABCB1 heterozygous patients than that in ABCB1 homozygous wild-type patients. CONCLUSIONS: Developmental pharmacogenetics of CYP2C19 was quantitatively described in neonates and young infants using omeprazole as a probe drug. Our findings emphasize the importance of semiphysiological developmental pharmacokinetic modelling approach when evaluating developmental pharmacogenetics of drugs with multiple routes of biotransformation.