Omeprazole disposition in children following single-dose administration

Abstract

Omeprazole is frequently used to treat gastroesophageal reflux in infants and children despite the lack of age-specific pharmacokinetic and dosing information in the approved product labeling. To address this challenge, the authors examined the potential influence of development and cytochrome P450 2C19 (CYP2C19) genotype on omeprazole disposition by conducting two pharmacokinetic (PK) studies in children and adolescents (ages 2-16 years) after a single oral 10- or 20-mg dose of the drug. Plasma omeprozole concentrations were determined by HPLC-MS from seven plasma samples obtained over a 6-hour postdose period. Pharmacokinetic parameters were determined by noncompartmental methods. Subjects were genotyped for CYP2C19 by PCR-RFLP. Data were available from 37 patients (19 female), 10 of whom were ≤ 5 years of age. No drug-associated adverse events were observed. The numbers of functional CYP2C19 alleles per subject in the cohort were 2 (n=25), 1 (n=11), and 0 (n=1). Pharmacokinetic parameters (mean ± SD, range) were as follows: tmax(2.1 ± 1.2, 1-6 h), Cmax (331.1 ± 333.6,20.8-885.8 ng/mL), AUC0 → ∞ (809.5 ± 893.8, 236.9-1330.9 ng/mL·h), t1/2 (0.98 ± 0.22, 0.7-1.4 h), and CL/F (1.8 ± 1.4, 0.3-5.8 L/h/kg). Comparison of mean AUC0 → ∞ values normalized for dose (i.e., per 1 mg/kg) between subjects with one versus two functional CYP2C19 alleles revealed no statistically significant difference. In addition, the CL/F and apparent elimination rate constant (λz) for omeprazole were not significantly different for subjects with one versus two functional CYP2C19 alleles. No association between age and CL/F, t1/2, or λz was observed. The range of t1/2 values for omeprazole was similar to those reported in adults (1-1.5 h). Conclusions: (1) in children ages 2 to 16 years receiving 10 or 20 mg of omeprazole as a single oral dose, the PK are quite comparable to values reported for adults, and (2) in pediatric patients who are CYP2C19 extensive metabolizers, there was no association between genotype and the pharmacokinetics of omeprazole. ©2003 the American College of Clinical Pharmacology.