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

Abstract

There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. Thirty each of HIV-infected patients on nevirapine-based antiretroviral therapy and HIV-negative volunteers without clinical malaria, but with predetermined CYP2B6 c.516GG and TT genotypes, were administered a complete treatment dose of 3 days of artemether-lumefantrine. Rich pharmacokinetic sampling prior to and following the last dose was conducted, and the plasma concentrations of artemether/dihydroartemisinin and lumefantrine/desbutyl-lumefantrine were quantified using tandem mass spectrometry. Pharmacokinetic parameters of artemether-lumefantrine and its metabolites in HIV-infected patients on nevirapine were compared to those in the absence of nevirapine in HIV-negative volunteers. Overall, nevirapine reduced exposure to artemether and desbutyl-lumefantrine by 39 and 34%, respectively. These reductions were significantly greater in GG versus TT subjects for artemether (ratio of geometric mean [90% confidence interval]: 0.42 [0.29 to 0.61] versus 0.81 [0.51 to 1.28]) and for desbutyl-lumefantrine (0.56 [0.43 to 0.74] versus 0.75 [0.56 to 1.00]). On the contrary, it increased exposure to dihydroartemisinin and lumefantrine by 47 and 30%, respectively. These increases were significantly higher in TT versus GG subjects for dihydroartemisinin (1.67 [1.20 to 2.34] versus 1.25 [0.88 to 1.78]) and for lumefantrine (1.51 [1.20 to 1.90] versus 1.08 [0.82 to 1.42]). This study underscores the importance of incorporating pharmacogenetics into all drug-drug interaction studies with potential for genetic polymorphisms to influence drug disposition.

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations—Implication for Drug Safety, Dosing, and Individualized Therapy

“…Another study amongst Nigerian HIV-malaria infected subjects explored the impact of CYP2B6 516GT polymorphism on NVR and artemether-lumefantrine drug-drug interaction. The authors showed that decreased exposure to artemether and desbutyl-lumefantrine caused by NVR was further enhanced by patients with CYP2B6 516GG genotype (ultrarapid metabolizers) (Abdullahi et al, 2020 ). Again, the CYP2B6 516TT genotype (poor metabolizers) also influenced increased exposure to dihydroartemisinin and lumefantrine caused by NVR (Abdullahi et al, 2020 ).…”

“…The authors showed that decreased exposure to artemether and desbutyl-lumefantrine caused by NVR was further enhanced by patients with CYP2B6 516GG genotype (ultrarapid metabolizers) (Abdullahi et al, 2020 ). Again, the CYP2B6 516TT genotype (poor metabolizers) also influenced increased exposure to dihydroartemisinin and lumefantrine caused by NVR (Abdullahi et al, 2020 ). According to the authors, the inductive effect of NRV on CYP2B6 and CYP3A4 enzymes, both of which are involved in the metabolism of these antimalarial drugs, might have caused this variability (Abdullahi et al, 2020 ).…”

“…Again, the CYP2B6 516TT genotype (poor metabolizers) also influenced increased exposure to dihydroartemisinin and lumefantrine caused by NVR (Abdullahi et al, 2020 ). According to the authors, the inductive effect of NRV on CYP2B6 and CYP3A4 enzymes, both of which are involved in the metabolism of these antimalarial drugs, might have caused this variability (Abdullahi et al, 2020 ). An Iranian study also indicated high prevalence of CYP2B6 * 2, * 4, * 5, * 6, and * 7 alleles among the Iranian Baluchi, which may affect patient response to artemisinin and derivatives (Zakeri et al, 2014 ).…”

The Manifesto of Pharmacoenosis: Merging HIV Pharmacology into Pathocoenosis and Syndemics in Developing Countries

“…Indeed, selecting regimen combinations based upon known underlying favourable enzymatic profiles able to compensate in the opposite direction potential unfavourable enzymatic induction/inhibition of DDIs may preserve treatment options, outcomes, and adherence by reducing concentrations below/above the therapeutic range. In this regard, recent data showed a differential impact of the co-administration of nevirapine and antimalarial regimens when stratified by CYP2B6 polymorphisms [ 49 ]: the nevirapine-induced reduction of artemether and desbutyl-lumefantrine and increase of dihydroartemisinin and lumefantrine significantly differed between CYP2B6 c516GG versus TT genotypes [ 49 ]. If geographical PG data were easily and widely available, population-physiologically-based PK modelling could classify the same co-administration as contraindicated in some areas while recommended or neutral in others.…”

Association between CYP2B6 c.516G >T variant and acute leukaemia

“…CYP2B6 gene is located in 19q12–13.2, with a total length of 27.1 kb, including 11 exons which encode 491 amino acids [22] . A number of variants have been found in CYP2B6 such as NM_000767.5:c.516G>T ( CYP2B6 c.516G>T) variant which affects the activity of CYP2B6, and reduces the rate of human transformation of carcinogenic substances into inactive metabolites, which leads to the accumulation of carcinogenic substances, and a series of diseases [23–26] …”