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

Olafuyi, Olusola, Coleman, Michael and Badhan, Raj K.S. (2017). 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. European Journal of Pharmaceutical Sciences, 106 , pp. 20-33.

Abstract

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: https://doi.org/10.1016/j.ejps.2017.05.043
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Life & Health Sciences > Chronic and Communicable Conditions
Life & Health Sciences > Cellular and Molecular Biomedicine
Life & Health Sciences > Applied Health Research Group
Additional Information: © 2017, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Uncontrolled Keywords: malaria,paediatrics,pharmacokinetics,physiologically-based pharmacokinetics,tuberculosis,Pharmacology, Toxicology and Pharmaceutics(all),Pharmaceutical Science
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2017-08-30
Authors: Olafuyi, Olusola
Coleman, Michael
Badhan, Raj K.S. ( 0000-0002-0904-9324)

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