Polymorphisms in genes have been found in most enzymes involved in drug metabolism, especially in the cytochrome P450 (CYP) family with considerable ethnic differences in their frequencies. Single nucleotide polymorphisms (SNPs) are the major source of these genetic variations. CYP2B6 516G>T SNP found in both CYP2B6*6 and CYP2B6*9 alleles significantly reduces CYP2B6 protein expression and enzyme activity with important implications on the pharmacokinetics and pharmacodynamic outcomes of some clinically relevant drug substrates. This study determined the frequencies of CYP2B6 516G>T SNP in HIV-negative and HIV-infected adult Nigerian populations. Three hundred unrelated subjects (150 each of HIV-negative volunteers and HIV-infected patients) of different Nigerian ethnic groups residing in Ilorin and Ile-Ife and its environs, respectively, were recruited and genotyped for their CYP2B6 516G>T genetic status using real-time polymerase chain reaction. Differences in allele and genotype frequencies between both populations were tested using Pearson χ test. Minor allele frequency of 36.4% and genotype frequencies of 38.7% GG, 50.0% GT, 11.3% TT and a minor allele frequency of 37.0% and genotype frequencies of 42.0% GG, 42.0% GT, 16.0% TT were obtained for the HIV-negative volunteers and HIV-infected patients, respectively. χ test indicated a significant relationship between genotype frequencies in both populations (P < 0.001). The minor allele and genotype frequencies obtained in the 2 populations significantly differ and corroborate previous studies, which have reported CYP2B6 516G>T SNP in various other African populations.

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.

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