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Titolo:
Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man
Autore:
Abelo, A; Gabrielsson, J; Holstein, B; Eriksson, UG; Holmberg, J; Karlsson, MO;
Indirizzi:
AstraZeneca AB, R&D Dept, S-43183 Molndal, Sweden AstraZeneca AB MolndalSweden S-43183 R&D Dept, S-43183 Molndal, Sweden Uppsala Univ, Uppsala, Sweden Uppsala Univ Uppsala SwedenUppsala Univ, Uppsala, Sweden
Titolo Testata:
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
fascicolo: 4, volume: 14, anno: 2001,
pagine: 339 - 346
SICI:
0928-0987(200112)14:4<339:PMORGA>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
SECRETION; OMEPRAZOLE;
Keywords:
PK/PD modelling; NONMEM; gastric acid secretion inhibition; reversible H+; K+-ATPase inhibitor;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
12
Recensione:
Indirizzi per estratti:
Indirizzo: Abelo, A AstraZeneca AB, R&D Dept, S-43183 Molndal, Sweden AstraZeneca ABMolndal Sweden S-43183 , S-43183 Molndal, Sweden
Citazione:
A. Abelo et al., "Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man", EUR J PH SC, 14(4), 2001, pp. 339-346

Abstract

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-timeprofile. Dose escalation studies were performed to characterize the effecton 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 appliedto 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 slowequilibration between free drug, free enzyme and drug-enzyme complex, described by a kinetic binding model, and (3) a delay between enzyme inhibitionand 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. The dissociation rate constant, k(off), was estimated to be 0.85 and 0.88 hand 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. (C) 2001 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/04/20 alle ore 23:54:42