Affiliations 

  • 1 Aston Health Research Group, Aston Pharmacy School, Aston University, Birmingham B4 7ET, United Kingdom; Ministry Of Health Malaysia, Block E1, E3, E6, E7 & E10, Parcel E, Federal Government Administration Centre, 62590 Putrajaya, Malaysia
  • 2 Aston Health Research Group, Aston Pharmacy School, Aston University, Birmingham B4 7ET, United Kingdom; Aston Pharmacy School, Aston University, Birmingham B4 7ET, United Kingdom. Electronic address: r.k.s.badhan@aston.ac.uk
Eur J Pharm Sci, 2018 Jul 01;119:90-101.
PMID: 29635009 DOI: 10.1016/j.ejps.2018.04.012

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 

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.