Dataset Information

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 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.

SUBMITTER: Fink C

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

REPOSITORIES: biostudies-literature

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

Fink Christina C Sun Dajun D Wagner Knut K Schneider Melanie M Bauer Holger H Dolgos Hugues H Mäder Karsten K Peters Sheila-Annie SA

Clinical pharmacology and therapeutics 20191121 3

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 misclassifi ...[more]

PMID: 31608434

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Project description:Background and objectivesPhysiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib.MethodsA PBPK model was built in GastroPlus® that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution.ResultsThe inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state.ConclusionsFully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection.

Dataset Information

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

Publications

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

Similar Datasets

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