The impact of CYP2B6 polymorphisms on the interactions of efavirenz with lumefantrine: Implications for paediatric antimalarial therapy

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Abstract

Lumefantrine is a widely used antimalarial in children in sub-Saharan Africa and is predominantly metabolised by CYP3A4. The concomitant use of lumefantrine with the antiretroviral efavirenz, which is metabolised by CYP2B6 and is an inducer of CYP3A4, increases the risk of lumefantrine failure and can result in an increased recrudescence rate in HIV-infected children. This is further confounded by CYP2B6 being highly polymorphic resulting in a 2–3 fold higher efavirenz plasma concentration in polymorphic subjects, which enhances the potential for an efavirenz-lumefantrine drug-drug interaction (DDI). This study developed a population-based PBPK model capable of predicting the impact of efavirenz-mediated DDIs on lumefantrine pharmacokinetics in African paediatric population groups, which also considered the polymorphic nature of CYP2B6. The validated model demonstrated a significant difference in lumefantrine target day 7 concentrations (Cd7) in the presence and absence of efavirenz and confirmed the capability of efavirenz to initiate this DDI. This was more apparent in the *6/*6 compared to *1/*1 population group and resulted in a significantly lower (P < 0.001) lumefantrine Cd7. A prospective change in dosing schedule from 3-days to 7-days resulted in a greater number of *6/*6 subjects (28–57%) attaining the target Cd7 across age bands (0.25–13 years), with the greatest increase evident in the 1–4 year old group (3-day: 1%; 7-day: 28%).

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  • The impact of CYP2B6 polymorphisms

    Rights statement: © 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

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Details

Original languageEnglish
Pages (from-to)90-101
JournalEuropean Journal of Pharmaceutical Sciences
Volume119
Early online date7 Apr 2018
DOIs
Publication statusE-pub ahead of print - 7 Apr 2018

Bibliographic note

© 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ The authors would like to thank the Ministry of Health Malaysia for providing funding for this project.

    Keywords

  • Physiologically-based pharmacokinetics, Malaria, HIV, Paediatrics, Africa

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