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

Abstract

AIMSIn 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. METHODSThis 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. RESULTSNo 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 À1 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). CONCLUSIONSThis 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. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2019) 85 540-550 540• Single nucleotide polymorphisms in disposition genes partly contribute to variability in nevirapine pharmacokinetics, with CYP2B6 c.516G>T and c.983T>C reported to increase its exposure. • Whereas impact of nevirapine on artemether-lumefantrine is well studied, limited studies have investigated the influence of artemether-lumefantrine on nevirapine pharmacokinetics and there are no data on the influence of CYP2B6 c.516G>T and c.983T>C on this interaction. WHAT THIS STUDY ADDS• This study introduces a novel approach that involved stratifying patients based on their metabolic status for clinical drug-drug interaction studies. • Irrespective of patient's CYP2B6 metabolic status, co-administration with artemether-lumefantrine is unlikely to result in any clinically significant changes in key nevirapine pharmacokinetics. However, the proportion of patients with trough plasma nevirapine concentration below the putative minimum effective concentration threshold doubled in the presence of artemether-lumefantrine, mainly in extensive metabolizers. PGt of artemether-lumefantrine vs. nevirapine DDI Br J Clin Pharmacol (2019) 85 540-550 541 PGt of artemether-lumefantrine vs. nevirapine DDI Br J Clin Pharmacol (2019) 85 540-550 549

Differential Impact of Nevirapine on Artemether-Lumefantrine Pharmacokinetics in Individuals Stratified by CYP2B6 c.516G>T Genotypes

“…Abbreviations: n, sample size; C max , maximum concentration; T max , time to reach C max ; AUC 0 -336 , area under the concentration time curve from 0 to 336 h; AUC 0 -∞ , AUC curve extrapolated to infinity; t 1/2 , terminal phase half-life; CL/F, oral clearance; day 6 (C day 6 ) and day 10 (C day 10 ) plasma concentrations. influenced by CYP2B6 polymorphisms (14,20,36). The overall 30% higher exposure to lumefantrine when not stratified to CYP2B6 c.516GϾT genotypes is consistent with data from previous similar parallel design studies (29,(32)(33)(34).…”

“…The results of this study showed that nevirapine-based ART phenotypically reduced artemether exposure with a corresponding rise in dihydroartemisinin exposure, as against the genotype-predicted rise in artemether and the reduction in dihydroartemisinin exposures in the absence of nevirapine, in CYP2B6 c.516TT subjects. In addition, although CYP2B6 is not the main enzyme responsible for the biotransformation of lumefantrine (10), the higher exposure to nevirapine of TT patients observed in our previously reported study (36) culminated in greater exposure to lumefantrine compared to their GG counterparts. Therefore, coadministration of nevirapine with artemether-lumefantrine favored higher exposures to the two principal determinants of antimalarial efficacy as dihydroartemisinin and lumefantrine exposures were approximately 4 and 46%, respectively, higher in TT than in GG patients (Tables 2 and 4).…”

“…Moreover, data on the impact of genetic polymorphisms on the drug-drug interactions between artemether-lumefantrine and nevirapine are sparse (35). We recently reported the influence of pharmacogenetic variations on the interaction of artemether-lumefantrine with nevirapine in a cohort of HIV-infected patients (36). In view of the conflicting reports and the increasing relevance of genetic polymorphisms to impact drug disposition, this study investigated influence of homozygous CYP2B6 c.516GϾT genotypes on the pharmacokinetic interaction of nevirapine with artemether-lumefantrine in HIV-infected Nigerian patients using HIV-negative volunteers as a control.…”

Trough plasma nevirapine levels, immunologic and virologic responses in composite CYP2B6*6/*18 HIV‐infected adult Nigerian patients

“…32 The patients were from a cohort of 150 HIV-infected patients previously genotyped and with measured plasma nevirapine levels. 30,33 The inclusion criteria were HIVpositive patients above 18 years of age on nevirapinebased ART combinations (of zidovudine + lamivudine or tenofovir + lamivudine or abacavir + lamivudine) with records of absolute lymphocyte count and CD4+ T lymphocyte counts over a period of at least a year. Patients with recent history of poor compliance according to pharmacy ART refill record were excluded.…”

“…[23][24][25][26][27][28][29] However, only a limited number of studies have reported influence of both genotypes on CD4+ T lymphocytes counts and HIV RNA levels. 25,27,28 We previously reported influence of composite CYP2B6*6/*18 genotype on the pharmacokinetics of nevirapine in the presence of artemether-lumefantrine in a subgroup of 30 HIV-infected patients 30 The present retrospective study evaluates the influence of composite CYP2B6*6/*18 genotype on the trough plasma nevirapine (the concentration immediately before the next dose is administered), and HIV RNA (virologic response) levels as well as on the absolute lymphocyte and CD4+ T lymphocyte counts (immunologic responses) in genetically defined groups of HIV-infected adult Nigerian patients on nevirapine-based ART combinations.…”