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 an d 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 a pplied to multiple-dose data from a crossover study of four dosage regimens of lansoprazole in two groups of normal male subjects. Model parameters we re estimated by nonlinear regression and were compared to historical values reported in the literature. The predicted mean gastric ion concentration w as 23.2 mM (pH 1.6) with the peak time at 22.6 hours (8:30 p.m.), and the h alf-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 norm al H+/K+-ATPase degradation was 0.045 h(-1). The pharmacodynamic parameter describing lansoprazole action on gastric acid secretion was the second-ord er enzyme inactivation constant, which averaged 0.16 mug.L.h(-1). The param eters obtained for both the baseline and drug treatment data were consisten t with the literature and physiologically relevant with the exception of ef fective food volume, which was large presumably due to buffer effects. The model successfully incorporated the physiological regulation of gastric aci d production, the effects of food on gastric acid, and the effects of multi ple-dosing regimens of lansoprazole on gastric acid production to give reas onable profiles of gastric pH. Journal of Clinical Pharmacology, 2001;41:25 2-258 (C) 2001 the American College of Clinical Pharmacology.