Development of a paediatric physiologically based pharmacokinetic model to assess the impact of drug-drug interactions in tuberculosis co-infected malaria subjects:a case study with artemether-lumefantrine and the CYP3A4-inducer rifampicin


The fixed dosed combination of artemether and lumefantrine (AL) is widely used for the treatment of malaria in adults and children in sub-Sahara Africa, with lumefantrine day 7 concentrations being widely used as a marker for clinical efficacy. Both are substrates for CYP3A4 and susceptible to drug-drug interactions (DDIs); indeed, knowledge of the impact of these factors is currently sparse in paediatric population groups. Confounding malaria treatment is the co-infection of patients with tuberculosis. The concomitant treatment of AL with tuberculosis chemotherapy, which includes the CYP3A4 inducer rifampicin, increases the risk of parasite recrudescence and malaria treatment failure. This study developed a population-based PBPK model for AL in adults capable of predicting the pharmacokinetics of AL under non-DDI and DDI conditions, as well as predicting AL pharmacokinetics in paediatrics of 2–12 years of age. The validated model was utilised to assess the concomitant treatment of rifampicin and lumefantrine under standard body-weight based treatment regimens for 2–5 year olds, and demonstrated that no subjects attained the target day 7 concentration (Cd7) of 280 ng/mL, highlighting the importance of this DDI and the potential risk of malaria-TB based DDIs. An adapted 7-day treatment regimen was simulated and resulted in 63% and 74.5% of subjects attaining the target Cd7 for 1-tablet and 2-tablet regimens respectively.

Publication DOI:
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Additional Information: © 2017, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Uncontrolled Keywords: malaria,paediatrics,pharmacokinetics,physiologically-based pharmacokinetics,tuberculosis,Pharmacology, Toxicology and Pharmaceutics(all),Pharmaceutical Science
Publication ISSN: 1879-0720
Last Modified: 25 Mar 2024 08:21
Date Deposited: 24 May 2017 10:35
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2017-08-30
Published Online Date: 2017-05-22
Accepted Date: 2017-05-20
Submitted Date: 2017-02-02
Authors: Olafuyi, Olusola
Coleman, Michael (ORCID Profile 0000-0002-5510-6852)
Badhan, Raj K.S. (ORCID Profile 0000-0002-0904-9324)

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