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A strategy for early-risk predictions of clinical drug–drug interactions involving the GastroPlusTM DDI module for time-dependent CYP inhibitors
- Source :
- Xenobiotica. 48:348-356
- Publication Year :
- 2017
- Publisher :
- Informa UK Limited, 2017.
-
Abstract
- 1. A set of reference compounds for time-dependent inhibition (TDI) of cytochrome P450 with available literature data for kinact and KI was used to predict clinical implications using the GastroPlusTM software. Comparisons were made to in vivo literature interaction data. 2. The predicted AUC ratios (AUC+inhibitor/AUCcontrol) 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 GastroPlusTM 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 GastroPlusTM, we have implemented an early TDI risk assessment decision tree for our drug discovery projects involving in vitro screening and early GastroPlusTM predictions. Shifted IC50 values are determined and kinact/KI estimated (by using a regression line established with in house-shifted IC50 values and literature kinact/KI ratios), followed by GastroPlusTM predictions.
- Subjects :
- Pharmacology
Drug
Chemistry
Health, Toxicology and Mutagenesis
media_common.quotation_subject
General Medicine
Toxicology
Multiple dosing
030226 pharmacology & pharmacy
Biochemistry
Telaprevir
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
In vivo
030220 oncology & carcinogenesis
Linear regression
medicine
Ic50 values
IC50
medicine.drug
media_common
Subjects
Details
- ISSN :
- 13665928 and 00498254
- Volume :
- 48
- Database :
- OpenAIRE
- Journal :
- Xenobiotica
- Accession number :
- edsair.doi...........d4d3cc5ccabbc24863b66243443c18d7