Revising Pharmacokinetics of Oral Drug Absorption: I Models Based on Biopharmaceutical/Physiological and Finite Absorpti
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RESEARCH PAPER
Revising Pharmacokinetics of Oral Drug Absorption: I Models Based on Biopharmaceutical/Physiological and Finite Absorption Time Concepts Panos Macheras 1,2,3
&
Pavlos Chryssafidis 1,3
Received: 1 June 2020 / Accepted: 24 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSRACT Purpose To demonstrate that oral drug absorption is terminated in finite time. To develop models based on biopharmaceutical/physiological and finite absorption time concepts. Methods The models are based on i) the passive drug diffusion mechanism under the sink conditions principle ii) the rate limiting role of the drug’s properties solubility and permeability and iii) the relevant restrictions associated with the gastrointestinal transit times of drug in the stomach, the small intestines and the colon. Two input functions of constant rate are considered for the absorption of drug from i) the stomach/ small intestines with an upper limit of 5 h and ii) the colon with an upper limit of 30 h. Branched differential equations were written for the time course of drug in the body. Results Simulations were performed using different scenarios, assuming a variety of drug properties and limited or non-existent absorption from the colon. Literature oral data of cephradine, ibuprofen, flurbiprofen and itraconazole were analyzed. For all drugs examined, nice fittings of the branched differential equations to the experimental data were observed. Conclusions For all drugs the absorption process was terminated in the small intestine. The meaning of partial AUCs, Cmax, tmax are questioned. Applications of these models to IVIVC are anticipated.
* Panos Macheras [email protected]
1
PharmaInformatics Unit, ATHENA Research Center, Athens, Greece
2
Department of Pharmaceutical Sciences, State University of New York (SUNY), Buffalo, New York, USA
3
Department of Pharmacy, National and Kapodistrian University of Athens, University Campus, 15771 Athens, Greece
KEY WORDS oral drug absorption . finite absorption time . pharmacokinetics, BCS, BDDCS
ABBREVIATIONS BCS BDDCS GI IVIVC PBFTPK PBPK
Biopharmaceutic classification system Biopharmaceutic drug disposition classification System Gastrointestinal In vitro in vivo correlations Physiologically based finite time pharmacokinetic Physiologically based pharmacokinetic
INTRODUCTION The oral route is the most common for drug administration. Extensive work in this field of research revealed that two basic drug properties, namely, solubility and permeability of gastrointestinal membrane determine the extent of oral drug absorption [1, 2]. These scientific advances lead to the development of the biopharmaceutic classification system (BCS), the biopharmaceutic drug disposition classification system (BDDCS) and the publication of relevant regulatory guidelines, by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [3, 4]. These guidelines formulate the scientific requirements for the performance or not of bioequivalence studies towards t
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