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Analysis of clinical drug-drug interaction data to predict uncharacterized interaction magnitudes between antiretroviral drugs and co-medications

Stader, Felix and Kinvig, Hannah and Battegay, Manuel and Khoo, Saye and Owen, Andrew and Siccardi, Marco and Marzolini, Catia. (2018) Analysis of clinical drug-drug interaction data to predict uncharacterized interaction magnitudes between antiretroviral drugs and co-medications. Antimicrobial agents and chemotherapy, 62 (7). e00717-18.

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Abstract

Despite their high potential for drug-drug interactions (DDI), clinical DDI studies of antiretroviral drugs (ARVs) are often lacking, because the full range of potential interactions cannot feasibly or pragmatically be studied, with some high-risk DDI studies also being ethically difficult to undertake. Thus, a robust method to screen and to predict the likelihood of DDIs is required. We developed a method to predict DDIs based on two parameters: the degree of metabolism by specific enzymes, such as CYP3A, and the strength of an inhibitor or inducer. These parameters were derived from existing studies utilizing paradigm substrates, inducers, and inhibitors of CYP3A to assess the predictive performance of this method by verifying predicted magnitudes of changes in drug exposure against clinical DDI studies involving ARVs. The derived parameters were consistent with the FDA classification of sensitive CYP3A substrates and the strength of CYP3A inhibitors and inducers. Characterized DDI magnitudes (; n; = 68) between ARVs and comedications were successfully quantified, meaning 53%, 85%, and 98% of the predictions were within 1.25-fold (0.80 to 1.25), 1.5-fold (0.66 to 1.48), and 2-fold (0.66 to 1.94) of the observed clinical data. In addition, the method identifies CYP3A substrates likely to be highly or, conversely, minimally impacted by CYP3A inhibitors or inducers, thus categorizing the magnitude of DDIs. The developed effective and robust method has the potential to support a more rational identification of dose adjustment to overcome DDIs, being particularly relevant in an HIV setting, given the treatment's complexity, high DDI risk, and limited guidance on the management of DDIs.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Infectious Disease Modelling > Disease and Intervention Dynamics (Penny)
UniBasel Contributors:Stader, Felix
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:05 Sep 2018 08:39
Deposited On:05 Sep 2018 08:39

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