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 irreversible 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 effect-time profile was delayed compared to the concentration-time profile. A model-based approach, using non-linear mixed effects modelling, was applied to quantify and elucidate the mechanism for the delayed effect. Three different models were investigated: (1) a slow equilibration preceding the formation of drug-enzyme complex, modelled by an effect-compartment, (2) a slow equilibration between free drug, free enzyme and drug-enzyme complex, described 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 1 and 3, for both dog and human data. The 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 and man, respectively. Simulations of the predicted time-course of the effect beyond the 4-5-h observation period was similar for the three models.
Abelö
A
A
AstraZeneca AB, R&D Department, S-431 83 Mölndal/Södertälje, Sweden. angela.abelo@astrazeneca.com
Gabrielsson
J
J
Holstein
B
B
Eriksson
U G
UG
Holmberg
J
J
Karlsson
M O
MO
D000284:Administration, Oral; D000328:Adult; D000634:Aminoquinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D008956:Models, Chemical; D017711:Nonlinear Dynamics; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000378:metabolism*
D000634:Aminoquinolines; D000962:Antimalarials; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; C001920:4-aminoquinoline