Objective: The aim of this study was to create a useful model of the effect of the area under the plasma concentration vs time curve (AUC) and the maximum plasma concentration (C(max)) of esomeprazole on intragastric pH, measured as the percentage of total time with intragastric pH above 4 (%pH>4) during a 24-h period.
Methods: The evaluation is based on esomeprazole data from two crossover studies. In the first study ( n=36), intragastric pH and plasma concentrations were measured on day 5 of repeated once-daily 20-mg and 40-mg doses of esomeprazole during fasting conditions. In the second study ( n=24), measurements were made on days 1 and 5 of repeated once-daily dosing with 40 mg of esomeprazole under fasting and fed conditions. A model was applied in which the logistic function of %pH>4 was assumed to be linearly dependent on log-transformed AUC and C(max). The effects of repeated dosing and of fed relative to fasting conditions were included in the model, and the interindividual variation in %pH>4 was accounted for.
Results: The effect of the pharmacokinetic variables AUC and C(max) of esomeprazole on %pH>4 can be adequately described by a model using a logistic function for %pH>4 and a normally distributed error. In this model, log-transformed AUC and C(max) were both statistically significant. The model showed that for a fixed AUC, a decrease in C(max) gives an increase in %pH>4. A decrease in AUC, keeping C(max) fixed, gives a decrease in %pH>4, but a simultaneous decrease in C(max) and AUC will result in a less pronounced decrease in %pH>4. The model may be used for predicting differences in %pH>4 between two formulations, based on assessments of AUC and C(max). Repeated dosing gave an increased %pH>4, where approximately half of the increase stemmed from increased AUC and C(max), and the rest could be attributable to the persistent blockade of the proton pumps. Food intake reduced AUC and C(max) but had no obvious effect on %pH>4, which is explained by a prolonged time period with quantifiable plasma concentrations.
Conclusion: The effect of the pharmacokinetic variables AUC and C(max) of esomeprazole on %pH>4 can be adequately described by a model using a logistic function for %pH>4 and a normally distributed error.