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Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
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2001 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 14, no 4, 339-346 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2001. Vol. 14, no 4, 339-346 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-91079DOI: 10.1016/S0928-0987(01)00187-7PubMedID: 11684409OAI: oai:DiVA.org:uu-91079DiVA: diva2:163669
Available from: 2003-11-20 Created: 2003-11-20 Last updated: 2011-11-30Bibliographically approved
In thesis
1. Pharmacodynamic Modelling of Irreversible and Reversible Gastric Proton Pump Inhibitors
Open this publication in new window or tab >>Pharmacodynamic Modelling of Irreversible and Reversible Gastric Proton Pump Inhibitors
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acid related diseases like GERD, duodenal-and gastric ulcers and H. Pylori-positive peptic ulcer disease are primarily managed by reducing gastric acidity. Irreversible proton pump inhibitors (PPIs) inhibit gastric acid secretion effectively throughout the day by irreversibly inhibiting the gastric proton pump, H+, K+-ATPase, in the parietal cells. Reversible gastric proton pump inhibitors are under development, but have not yet reached clinical use.

The pharmacokinetic/pharmacodynamic (PK/PD) relationships of these compounds are nonlinear, with a delay in the effect-time profile compared to the plasma concentration-time course. PK/PD-modelling was used to characterize and quantify the pharmacological effect with regard to onset, intensity and duration of effect. Models based on functional data, that discriminate between drug-and system-specific parameters, were developed.

In general, the plasma concentration-time course for each individual was approximated by linear interpolation between time-points and served as input into the pharmacodynamic models. A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog described the data well. The model was challenged and found to be robust under different experimental conditions. This model could predict the effect following different exposure of omeprazole and following different histamine provocation. Different fitting approaches (naïve pooling, standard two-stage and nonlinear mixed effects modelling) were compared and resulted in similar parameter estimates. For the reversible inhibitors, a kinetic binding model was finally selected. With a binding model the delay in the effect-time profile is explained by prolonged binding to the enzyme.

Use of these results in drug development can be helpful with regard to selection of drugs for further development and to predict the first clinical dose.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 47 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 303
Pharmacokinetics/Pharmacotherapy, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-3778 (URN)91-554-5806-8 (ISBN)
Public defence
2003-12-12, B22, Uppsala Biomedical Centre, Uppsala, 09:15
Available from: 2003-11-20 Created: 2003-11-20Bibliographically approved

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