A strategy for early-risk predictions of clinical drug-drug interactions involving the GastroPlus TM DDI module for time-dependent CYP inhibitors.

Autor: Sohlenius-Sternbeck AK; a DMPK and Bioanalysis, Medivir AB , Sweden., Meyerson G; a DMPK and Bioanalysis, Medivir AB , Sweden., Hagbjörk AL; a DMPK and Bioanalysis, Medivir AB , Sweden., Juric S; a DMPK and Bioanalysis, Medivir AB , Sweden., Terelius Y; a DMPK and Bioanalysis, Medivir AB , Sweden.
Jazyk: angličtina
Zdroj: Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 2018 Apr; Vol. 48 (4), pp. 348-356. Date of Electronic Publication: 2017 May 15.
DOI: 10.1080/00498254.2017.1323136
Abstrakt: 1. A set of reference compounds for time-dependent inhibition (TDI) of cytochrome P450 with available literature data for k inact and K I was used to predict clinical implications using the GastroPlus TM software. Comparisons were made to in vivo literature interaction data. 2. The predicted AUC ratios (AUC +inhibitor /AUC control ) could be compared with the observed ratios from literature for all compounds with detailed information about in vivo administration, pharmacokinetics and in vivo interactions (N = 21). For this dataset, the difference between predicted and observed AUC ratios for interactions with midazolam was within twofold for all compounds except one (telaprevir, for which non-CYP-mediated metabolism likely plays a role after multiple dosing). 3. The sensitivity, specificity and accuracy of the GastroPlus TM predictions using a binary classification as no-to-weak interaction versus moderate-to-strong interaction for all compounds with available in vivo interaction data, were 80%, 82% and 81%, respectively (N = 31). 4. As a result of our evaluations of the DDI module in GastroPlus TM , we have implemented an early TDI risk assessment decision tree for our drug discovery projects involving in vitro screening and early GastroPlus TM predictions. Shifted IC 50 values are determined and k inact /K I estimated (by using a regression line established with in house-shifted IC 50 values and literature k inact /K I ratios), followed by GastroPlus TM predictions.
Databáze: MEDLINE
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