The impact of CYP2B6 polymorphisms on the interactions of efavirenz with lumefantrine: Implications for paediatric antimalarial therapy
| Autor: | Raj K.S. Badhan, Zaril Zakaria |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Cyclopropanes 0301 basic medicine Efavirenz Adolescent CYP2B6 Anti-HIV Agents 030106 microbiology Population Pharmaceutical Science HIV Infections Pharmacology Lumefantrine Models Biological 030226 pharmacology & pharmacy Antimalarials Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics medicine Humans Computer Simulation Drug Interactions Dosing Child education Fluorenes education.field_of_study Polymorphism Genetic business.industry Infant virus diseases Middle Aged medicine.disease Benzoxazines Malaria Cytochrome P-450 CYP2B6 chemistry Ethanolamines Alkynes Child Preschool Concomitant business |
| Zdroj: | European Journal of Pharmaceutical Sciences. 119:90-101 |
| ISSN: | 0928-0987 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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