High-dose omeprazole: use of a multiple-dose study design to assess bioequivalence and accuracy of CYP2C19...

The objectives of this multiple-dose study were to compare the performance of a new formulation of omeprazole (40 mg) with that of an established formulation and to assess the accuracy of CYP2C19 phenotyping during high-dose chronic administration. Twenty-eight healthy subjects were randomized (1:1) to receive 40 mg of either Gasec-40 Gastrocaps (Mepha) or Antra 40 (Astra) daily for 5 days. The pharmacokinetics of omeprazole and the omeprazole/5'-hydroxyomeprazole ratio 3 hours postdose were assessed on day 5. Subjects switched formulations starting on day 6, and all measurements were repeated on day 8. Subjects with metabolic ratios greater than 6 were genotyped for CYP2C19. Gasec-40 was found to be bioequivalent to Antra based on the 90% confidence interval for AUC (102.4-111.7) and Cmax (100.6-120.7). Formulation had no effect on the ratio of omeprazole to 5'-hydroxyomeprazole, which was higher than previously reported with single 20 mg doses of omeprazole. The mean ratio did not differ between day 5 and day 8 but was highly variable: 7 of 28 subjects had more than a 2-fold difference between assessments. In four individuals identified by genotype as extensive metabolizers (EMs), phenotype could not be clearly assigned. The relative bioavailability of omeprazole can be accurately assessed using this multiple-dose study design. Chronic administration of 40 mg doses of omeprazole shifts the metabolic ratio in EMs toward that in poor metabolizers (PMs), apparently because of the nonlinear metabolic clearance of the drug. The assignment of phenotype in patients receiving chronic high-dose omeprazole treatment should be interpreted with caution.