Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man

H 335/25, a 4-amino quinoline, belongs to a new class of reversible gastric acid pump inhibitors. A potential advantage of such drugs over the irrever sible proton pump inhibitors (PPIs) is better control over the effect-time profile. Dose escalation studies were performed to characterize the effect on acid secretion in dogs (n=24) and healthy male subjects (n=12). The effe ct-time profile was delayed compared to the concentration-time profile. A m odel-based approach, using non-linear mixed effects modelling, was applied to quantify and elucidate the mechanism for the delayed effect. Three diffe rent models were investigated: (1) a slow equilibration preceding the forma tion of drug-enzyme complex, modelled by an effect-compartment, (2) a slow equilibration between free drug, free enzyme and drug-enzyme complex, descr ibed by a kinetic binding model, and (3) a delay between enzyme inhibition and the measured response, described by an indirect response model. Model 2 was shown to be superior to models I and 3, for both dog and human data. T he dissociation rate constant, k(off), was estimated to be 0.85 and 0.88 h and the calculated equilibration constant, K-d, was 160 and 250 nM in dog a nd man, respectively. Simulations of the predicted time-course of the effec t beyond the 4-5-h observation period was similar for the three models. (C) 2001 Elsevier Science B.V. All rights reserved.