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A Mechanistic Absorption and Disposition Model of Ritonavir to Predict Exposure and Drug–Drug Interaction Potential of CYP3A4/5 and CYP2D6 Substrates

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Abstract

Background and Objectives

Due 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.

Methods

A 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.

Results

Maximal 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 (Cmax) and area under the plasma concentration versus time curve (AUC) were assessed. The bias (average fold error, AFE) for the prediction of Cmax and AUC was 0.92 and 1.06, respectively, and the precision (absolute average fold error, AAFE) was 1.29 and 1.23, respectively. The PBPK model predictions for all Cmax and AUC ratios when ritonavir was used as an inhibitor of CYP metabolism fell within twofold of the clinical observations. The prediction accuracy for Cmax and AUC ratios had a bias (AFE) of 0.85 and 0.99, respectively, and a precision (AAFE) of 1.21 and 1.33, respectively.

Conclusions

The 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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Acknowledgements

The authors would like to thank Eleanor Savill for assistance with submitting the manuscript.

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Authors and Affiliations

  1. Certara UK Limited, Simcyp Division, Level 2 Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK

    Sumit Arora, Amita Pansari, Peter J. Kilford, Masoud Jamei, David B. Turner & Iain Gardner

  2. Janssen Pharmaceutical, Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium

    Sumit Arora

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  1. Sumit Arora
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  2. Amita Pansari
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Corresponding authors

Correspondence to Sumit Arora or Peter J. Kilford.

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Funding

The activities of Certara UK, Simcyp Division are supported by the Simcyp Consortium of pharmaceutical companies. No other source of funding was used for the work.

Conflict of interest

At the time of the work, Sumit Arora was employed by Certara UK Limited and may hold shares in the company. At the time of the work, Peter Kilford was employed by Certara UK Limited and may hold shares in the company. Amita Pansari is employed by Certara UK Limited and may hold shares in the company. David Turner is employed by Certara UK Limited and may hold shares in the company. Iain Gardner is employed by Certara UK Limited and may hold shares in the company. Masoud Jamei is employed by Certara UK Limited and may hold shares in the company.

Author Contributions

SA, PK, AP, DT, IG, and MJ wrote the manuscript; SA, AP, and PK designed the research; SA, AP, PK, and IG performed the research; SA, AP, PK, and IG analysed the data.

Ethics approval

This was a simulation study and did not involve any clinical studies, and therefore ethics approval was not needed.

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Not applicable.

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Not applicable.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability

The workspaces used to run the simulation are available from the corresponding author on reasonable request.

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Arora, S., Pansari, A., Kilford, P.J. et al. A Mechanistic Absorption and Disposition Model of Ritonavir to Predict Exposure and Drug–Drug Interaction Potential of CYP3A4/5 and CYP2D6 Substrates. Eur J Drug Metab Pharmacokinet 47, 483–495 (2022). https://doi.org/10.1007/s13318-022-00765-w

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