Pharmacogenetics of artemether-lumefantrine influence on nevirapine disposition: Clinically significant drug-drug interaction?

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  • Additional Information
    • Source:
      Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 7503323 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2125 (Electronic) Linking ISSN: 03065251 NLM ISO Abbreviation: Br J Clin Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Wiley-Blackwell
      Original Publication: London, Macmillan Journals Ltd.
    • Subject Terms:
      Antimalarials/*pharmacokinetics ; Artemether, Lumefantrine Drug Combination/*pharmacokinetics ; HIV Infections/*drug therapy ; Malaria/*drug therapy ; Nevirapine/*pharmacokinetics ; Reverse Transcriptase Inhibitors/*pharmacokinetics; Adult ; Antimalarials/administration & dosage ; Artemether, Lumefantrine Drug Combination/administration & dosage ; Cross-Over Studies ; Cytochrome P-450 CYP2B6/genetics ; Drug Interactions ; Female ; HIV Infections/blood ; HIV Infections/complications ; Humans ; Malaria/complications ; Male ; Middle Aged ; Nevirapine/administration & dosage ; Nigeria ; Polymorphism, Single Nucleotide ; Reverse Transcriptase Inhibitors/administration & dosage
    • Abstract:
      Aims: In this study the influence of first-line antimalarial drug artemether-lumefantrine on the pharmacokinetics of the antiretroviral drug nevirapine was investigated in the context of selected single nucleotide polymorphisms (SNPs) in a cohort of adult HIV-infected Nigerian patients.
      Methods: This was a two-period, single sequence crossover study. In stage 1, 150 HIV-infected patients receiving nevirapine-based antiretroviral regimens were enrolled and genotyped for seven SNPs. Sparse pharmacokinetic sampling was conducted to identify SNPs independently associated with nevirapine plasma concentration. Patients were categorized as poor, intermediate and extensive metabolizers based on the numbers of alleles of significantly associated SNPs. Intensive sampling was conducted in selected patients from each group. In stage 2, patients received standard artemether-lumefantrine treatment with nevirapine, and intensive pharmacokinetic sampling was conducted on day 3.
      Results: No clinically significant changes were observed in key nevirapine pharmacokinetic parameters, the 90% confidence interval for the measured changes falling completely within the 0.80-1.25 no-effect boundaries. However, the number of patients with trough plasma nevirapine concentration below the 3400 ng ml -1 minimum effective concentration increased from 10% without artemether-lumefantrine (all extensive metabolizers) to 21% with artemether-lumefantrine (14% extensive, 4% intermediate, and 3% poor metabolizers).
      Conclusions: This approach highlights additional increase in the already existing risk of suboptimal trough plasma concentration, especially in extensive metabolizers when nevirapine is co-administered with artemether-lumefantrine.
      (© 2018 The British Pharmacological Society.)
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    • Grant Information:
      MR/L006758/1 United Kingdom MRC_ Medical Research Council
    • Contributed Indexing:
      Keywords: CYP2B6; artemether-lumefantrine; drug-drug interaction; nevirapine; pharmacogenetics
    • Accession Number:
      0 (Antimalarials)
      0 (Artemether, Lumefantrine Drug Combination)
      0 (Reverse Transcriptase Inhibitors)
      99DK7FVK1H (Nevirapine)
      EC 1.14.14.1 (CYP2B6 protein, human)
      EC 1.14.14.1 (Cytochrome P-450 CYP2B6)
    • Publication Date:
      Date Created: 20181125 Date Completed: 20200207 Latest Revision: 20210109
    • Publication Date:
      20221213
    • Accession Number:
      PMC6379214
    • Accession Number:
      10.1111/bcp.13821
    • Accession Number:
      30471138