Pharmacodynamic modeling of lansoprazole using an indirect irreversible response model

A mechanism-based pharmacokinetic/pharmacodynamic model was used to assess lansoprazole effects on gastric pH. The irreversible inactivation of the H+/K+-ATPase enzyme by lansoprazole controls the secretion rate of H+ ions and gastric pH values. The basal circadian rhythm of gastric acid production was taken into account as well as the effects of food intake. A model was applied to multiple-dose data from a crossover study of four dosage regimens of lansoprazole in two groups of normal male subjects. Model parameters were estimated by nonlinear regression and were compared to historical values reported in the literature. The predicted mean gastric ion concentration was 23.2 mM (pH 1.6) with the peak time at 12.6 hours (8:30 p.m.), and the half-time for H+ removal from the stomach averaged 1.7 hours. The estimated half-life of gastric food removal was 0.8 hours. The rate constant for normal H+/K+-ATPase degradation was 0.045 h(-1). The pharmacodynamic parameter describing lansoprazole action on gastric acid secretion was the second-order enzyme inactivation constant, which averaged 0.16 microg(-1) x L x h(-1). The parameters obtained for both the baseline and drug treatment data were consistent with the literature and physiologically relevant with the exception of effective food volume, which was large presumably due to buffer effects. The model successfully incorporated the physiological regulation of gastric acid production, the effects of food on gastric acid, and the effects of multiple-dosing regimens of lansoprazole on gastric acid production to give reasonable profiles of gastric pH.
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