Population pharmacokinetic analysis of esomeprazole in Japanese subjects with various CYP2C19 phenotypes

Abstract

What is known and objective Esomeprazole, the S‐isomer of omeprazole, is a proton pump inhibitor which has been approved by over 125 countries, also known as NEXIUM®. Esomeprazole was developed to provide further improvement on efficacy for acid‐related diseases with higher systemic bioavailability due to the less first‐pass metabolism and lower plasma clearance. Esomeprazole is primarily metabolized by CYP2C19. Approximately <1% of Caucasians and 5%‐10% of Asians have absent CYP2C19 enzyme activity. Although the influence of various CYP2C19 phenotypes on esomeprazole pharmacokinetics has been studied, this is the first report in the Japanese population where 27 low CYP2C19 metabolizers were included. Methods In this study, a population PK model describing the PK of esomeprazole was developed to understand the difference of CYP2C19 phenotypes on clearance in the Japanese population. The model quantitatively assessed the influence of CYP2C19 phenotype on esomeprazole PK in healthy Japanese male subjects after receiving repeated oral dosing. The inhibition mechanism of esomeprazole on CYP2C19 activity was also included in the model. Results and discussion CYP2C19 phenotype and dose were found as statistically significant covariates on esomeprazole clearance. The apparent clearance at 10‐mg dose was 17.32, 9.77 and 7.37 (L/h) for homozygous extensive metabolizer, heterozygous extensive metabolizer and poor metabolizer subjects, respectively. And the apparent clearance decreased as dose increased. What is new and conclusion The established population PK model well described the esomeprazole PK and model‐predicted esomeprazole PK was in good agreement with external clinical data, suggesting the robustness and applicability of the current model for predicting esomeprazole PK.

Population pharmacokinetics of esomeprazole in patients with preterm preeclampsia

“…Esomeprazole disposition has mostly been described in literature with one-compartment kinetics for oral data and two-compartment kinetics for IV data. 24,25 Two-compartment disposition showed better fit in our model, similar to a model by Standing et al . 26 We estimated a typical clearance which was more than three times higher in extensive metabolizers compared to poor metabolizers This finding is consistent with previous reports that poor metabolizers have up to three times higher exposure than extensive metabolizers.…”

“…26 The typical central apparent volume of distribution of 14.9 L in our study is similar to that found in healthy individuals (˜16 L). 24,27 High variability in speed of absorption was observed in our model, likely due to differences in gastric acidity between-individuals and occasions. 24 Our study shows that esomeprazole clearance is lower during pregnancy which is probably due to CYP2C19 downregulation.…”

“…24,27 High variability in speed of absorption was observed in our model, likely due to differences in gastric acidity between-individuals and occasions. 24 Our study shows that esomeprazole clearance is lower during pregnancy which is probably due to CYP2C19 downregulation. This has several implications: first, metabolism during pregnancy may be more dependent on CYP3A4, which could mean there is less need for CYP2C19 genotyping during pregnancy, which has previously been suggested for proton pump inhibitors due to genotype-dependent variations in exposure and therapeutic/adverse outcomes.…”

“…3,4 Our estimate of clearance in poor metabolizers agrees with models by Nagase et al . 24 and Standing et al . 26 The typical central apparent volume of distribution of 14.9 L in our study is similar to that found in healthy individuals (˜16 L).…”

“…5,29 We don't expect as high of a nonlinear increase in exposure during pregnancy since metabolism could be CYP3A4-dependent, which is generally considered linear. 5,24,29 It was a limitation in our study that we couldn't isolate the actual effect of pregnancy and repeated dosing because there were other factors that were different between the studies, such as mealtimes and formulation, which could affect the absorption of esomeprazole. However, we believe that with the available data, our model can adequately describe changes during pregnancy and repeated dosing.…”