ArticleEuropean journal of drug metabolism and pharmacokinetics2022
A Mechanistic Absorption and Disposition Model of Ritonavir to Predict Exposure and Drug-Drug Interaction Potential of CYP3A4/5 and CYP2D6 Substrates.
Article in European journal of drug metabolism and pharmacokinetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 9 citations in OpenAlex.
- Review
- Physiologically Based Pharmacokinetic Modeling to Assess Ritonavir-Digoxin Interactions and Recommendations for Co-Administration Regimens.Pharmaceutical research · 2024Article
- Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report.Molecular pharmaceutics · 2024Review
- Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Quality assessment of oral antimalarial and antiretroviral medicines used by public health systems in Sahel countries.PloS one · 2024Article
- Interactions of the protease inhibitor, ritonavir, with common anesthesia drugs.Paediatric anaesthesia · 2022Review
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
objectivesDue to health authority warnings and the recommended limited use of ketoconazole as a model inhibitor of cytochrome P450 (CYP) 3A4 in clinical drug-drug interaction (DDI) studies, there is a need to search for alternatives. Ritonavir is a strong inhibitor for CYP3A4/5-mediated DDIs and has been proposed as a suitable alternative to ketoconazole. It can also be used as a weak inhibitor for CYP2D6-mediated DDIs. Most of the currently available physiologically based pharmacokinetic (PBPK) inhibitor models developed for predicting DDIs use first-order absorption models, which do not mechanistically capture the effect of formulations on the systemic exposure of the inhibitor. Thus, the main purpose of the current study was to verify the predictive performance of a mechanistic absorption and disposition model of ritonavir when it was applied to the inhibition of CYP2D6 and CYP3A4/5 by ritonavir.
methodsA PBPK model that incorporates formulation characteristics and enzyme kinetic parameters for post-absorptive pharmacokinetic processes of ritonavir was constructed. Key absorption-related parameters in the model were determined using mechanistic modelling of in vitro biopharmaceutics experiments. The model was verified for systemic exposure and DDI risk assessment using clinical observations from 13 and 18 studies, respectively.
resultsMaximal inhibition of hepatic (3.53% of the activity remaining) and gut (5.16% of the activity remaining) CYP3A4 activity was observed when ritonavir was orally administered in doses of 100 mg or higher. The PBPK model accurately described the concentrations of ritonavir in the different simulated studies. The prediction accuracy for maximum concentration (C
conclusionsThe current model, which incorporates formulation characteristics and mechanistic disposition parameters, can be used to assess the DDI potential of CYP3A4/5 and CYP2D6 substrates administered with a twice-daily dose of 100 mg of ritonavir for 14 days.
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