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Evaluating the Role of Solubility in Oral Absorption of Poorly Water‐Soluble Drugs Using Physiologically‐Based Pharmacokinetic Modeling
Author(s) -
Fink Christina,
Sun Dajun,
Wagner Knut,
Schneider Melanie,
Bauer Holger,
Dolgos Hugues,
Mäder Karsten,
Peters SheilaAnnie
Publication year - 2020
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1672
Subject(s) - solubility , drug , pharmacokinetics , in vivo , pharmacology , water soluble , drug development , chemistry , drug discovery , bioavailability , absorption (acoustics) , physiologically based pharmacokinetic modelling , medicine , microbiology and biotechnology , biochemistry , materials science , biology , organic chemistry , composite material
Poor aqueous solubility and dissolution of drug candidates drive key decisions on lead series optimization during drug discovery, on formulation optimization, and clinical studies planning during drug development. The interpretation of the in vivo relevance of early pharmaceutical profiling is often confounded by the multiple factors affecting oral systemic exposure. There is growing evidence that in vitro drug solubility may underestimate the true in vivo solubility and lead to drug misclassification. Based on 10 poorly water‐soluble tyrosine kinase inhibitors, this paper demonstrates the use of physiologically‐based pharmacokinetic (PK) analysis in combination with early clinical PK data to identify drugs whose absorption is truly limited by solubility in vivo and, therefore, expected to exhibit food effect. Our study supports a totality of evidence approach using early clinical data to guide decisions on conducting drug interaction studies with food and acid‐reducing agents.