Evaluating the Role of Solubility in Oral Absorption of Poorly Water-Soluble Drugs Using Physiologically-Based Pharmacokinetic Modeling.

ABSTRACT: 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

SUBMITTER: Fink C 

PROVIDER: S-EPMC7158207 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature