期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 101, 期 3, 页码 1267-1280出版社
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.22825
关键词
modeling; simulation; prediction; gastrointestinal tract; absorption; dosage forms; pharmacokinetics; PBPK; dissolution; Computational ADME
The physiological absorption model presented in part I of this work is now extended to account for dosage-form-dependent gastrointestinal (GI) transit as well as disintegration and dissolution processes of various immediate-release and modified-release dosage forms. Empirical functions of the Weibull type were fitted to experimental in vitro dissolution profiles of solid dosage forms for eight test compounds (aciclovir, caffeine, cimetidine, diclofenac, furosemide, paracetamol, phenobarbital, and theophylline). The Weibull functions were then implemented into the model to predict mean plasma concentrationtime profiles of the various dosage forms. On the basis of these dissolution functions, pharmacokinetics (PK) of six model drugs was predicted well. In the case of diclofenac, deviations between predicted and observed plasma concentrations were attributable to the large variability in gastric emptying time of the enteric-coated tablets. Likewise, oral PK of furosemide was found to be predominantly governed by the gastric emptying patterns. It is concluded that the revised model for GI transit and absorption was successfully integrated with dissolution functions of the Weibull type, enabling prediction of in vivo PK profiles from in vitro dissolution data. It facilitates a comparative analysis of the parameters contributing to oral drug absorption and is thus a powerful tool for formulation design. (c) 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:12671280, 2012
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