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


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%).

Publication DOI:
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > Applied Health Research Group
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: © 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International The authors would like to thank the Ministry of Health Malaysia for providing funding for this project.
Uncontrolled Keywords: Physiologically-based pharmacokinetics,Malaria,HIV,Paediatrics,Africa
Full Text Link:
Related URLs: https://www.sci ... 928098718301696 (Publisher URL)
PURE Output Type: Article
Published Date: 2018-07-01
Published Online Date: 2018-04-07
Accepted Date: 2018-04-05
Authors: Zakaria, Zaril Harza
Badhan, Raj K.S. (ORCID Profile 0000-0002-0904-9324)

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