Carrara, L; Magni, P; Teutonico, D; Pasotti, L; Pasqua, OD; Kloprogge, F; (2020) Ethambutol disposition in humans: challenges and limitations of whole-body physiologically-based pharmacokinetic modelling in early drug development. European Journal of Pharmaceutical Sciences , 150 , Article 105359. 10.1016/j.ejps.2020.105359.

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Abstract

Whole-body physiologically based pharmacokinetic (WB-PBPK) models have become an important tool in drug development, as they enable characterization of pharmacokinetic profiles across different organs based on physiological (systems specific) and physicochemical (drug specific) properties. However, it remains unclear which data are needed for accurate predictions when applying the approach to novel candidate molecules progressing into the clinic. In this work, as case study, we investigated the predictive performance of WB-PBPK models both for prospective and retrospective evaluation of the pharmacokinetics of ethambutol, considering scenarios that reflect different stages of development, including settings in which the data are limited to in vitro experiments, in vivo preclinical data, and when some clinical data are available. Overall, the accuracy of PBPK model predicted systemic and tissue exposure was heavily dependent on prior knowledge about the eliminating organs. Whilst these findings may be specific to ethambutol, the challenges and potential limitations identified here may be relevant to a variety of drugs, raising questions about 1) the minimum requirements for prospective use of WB-PBPK models during the characterization of drug disposition and 2) implication of uncertainty for dose selection in humans.

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