Search: (WFRF:(Eriksson Johan G.)) srt2:(2000-2009)
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Pharmacodynamic mod...
Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man
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- Äbelö, Angela (author)
- Uppsala universitet,Avdelningen för farmakokinetik och läkemedelsterapi
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Gabrielsson, Johan (author)
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Holstein, Björn (author)
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Eriksson, Ulf G (author)
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Holmberg, Johan (author)
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- Karlsson, Mats O. (author)
- Uppsala universitet,Avdelningen för farmakokinetik och läkemedelsterapi,Farmakometri
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(creator_code:org_t)
- 2001
- 2001
- English.
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In: European Journal of Pharmaceutical Sciences. - 0928-0987 .- 1879-0720. ; 14:4, s. 339-346
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
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- ref (subject category)
- art (subject category)
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