| Autor: |
Antunes NJ; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas 13083-881, SP, Brazil., Moreira FL; Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil., Kipper K; Institute of Chemistry, University of Tartu, 14a Ravila Street, 50411 Tartu, Estonia., Couchman L; Analytical Services International (ASI) Ltd., St George's-University of London, Cranmer Terrace, London SW17 0RE, UK.; Pharmaceutical Sciences Clinical Academic Group, King's College London, London SE1 9NH, UK., Lebre DT; Center for Applied Mass Spectrometry (CEMSA), São Paulo 05508-000, SP, Brazil., Johnston A; Analytical Services International (ASI) Ltd., St George's-University of London, Cranmer Terrace, London SW17 0RE, UK.; Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK., De Nucci G; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas 13083-881, SP, Brazil.; Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil.; Faculty of Medicine, São Leopoldo Mandic (SLMANDIC), Campinas 13045-755, SP, Brazil. |
| Abstrakt: |
This study predicted dapaconazole clinical drug−drug interactions (DDIs) over the main Cytochrome P450 (CYP) isoenzymes using static (in vitro to in vivo extrapolation equation, IVIVE) and dynamic (PBPK model) approaches. The in vitro inhibition of main CYP450 isoenzymes by dapaconazole in a human liver microsome incubation medium was evaluated. A dapaconazole PBPK model (Simcyp version 20) in dogs was developed and qualified using observed data and was scaled up for humans. Static and dynamic models to predict DDIs following current FDA guidelines were applied. The in vitro dapaconazole inhibition was observed for all isoforms investigated, including CYP1A2 (IC50 of 3.68 µM), CYP2A6 (20.7 µM), 2C8 (104.1 µM), 2C9 (0.22 µM), 2C19 (0.05 µM), 2D6 (0.87 µM), and 3A4 (0.008−0.03 µM). The dynamic (PBPK) and static DDI mechanistic model-based analyses suggest that dapaconazole is a weak inhibitor (AUCR > 1.25 and <2) of CYP1A2 and CYP2C9, a moderate inhibitor (AUCR > 2 and <5) of CYP2C8 and CYP2D6, and a strong inhibitor (AUCR ≥ 5) of CYP2C19 and CYP3A, considering a clinical scenario. The results presented may be a useful guide for future in vivo and clinical dapaconazole studies. |
