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

Abdullahi, Sa'ad T, Soyinka, Julius O, Olagunju, Adeniyi ORCID: 0000-0002-6588-5749, Bolarinwa, Rahman A, Olarewaju, Olusola J, Bakare-Odunola, Moji T, Winterberg, Markus, Tarning, Joel, Owen, Andrew ORCID: 0000-0002-9819-7651 and Khoo, Saye ORCID: 0000-0002-2769-0967 (2020) Differential Impact of Nevirapine on Artemether-Lumefantrine Pharmacokinetics in Individuals Stratified by CYP2B6 c.516G>T Genotypes. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 64 (3). e00947-e00919.

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Official URL: http://dx.doi.org/10.1128/aac.00947-19

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.

Item Type:	Article
Uncontrolled Keywords:	artemether-lumefantrine, nevirapine, pharmacokinetics, genetic polymorphisms, CYP2B6, malaria, HIV, human immunodeficiency virus
Depositing User:	Symplectic Admin
Date Deposited:	19 Feb 2020 14:52
Last Modified:	25 Jan 2024 06:34
DOI:	10.1128/AAC.00947-19
Open Access URL:	https://aac.asm.org/content/aac/early/2019/12/17/A...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3075737