Pharmacokinetics of Efavirenz When Co‐administered With Rifampin in TB/HIV Co‐infected Patients: Pharmacogenetic Effect of CYP2B6 Variation

Abstract

The goal of this study was to determine the effect of CYP2B6 genetic variation on the steady-state pharmacokinetics of efavirenz (600 mg/day) in TB/HIV co-infected patients receiving concomitant rifampin, a potent CYP inducer. In the 26 patients studied, CYP2B6 c.516GG, GT and TT genotype frequencies were 0.27, 0.50 and 0.23, respectively. Mean plasma efavirenz area-under-the-curve was significantly higher in patients with CYP2B6 c.516TT than in those with GT (107 vs. 27.6 μg.h/mL, P < 0.0001), or GG genotype (107 vs. 23.0 μg.h/mL, P < 0.0001). Apparent oral clearance (CL/F) was significantly lower in patients with CYP2B6 c.516TT than in those with GT genotype (2.1 vs. 8.4 mL/min/kg, P < 0.0001), and GG genotype (2.1 vs. 9.9 mL/min/kg, P < 0.0001). No differences in efavirenz exposure or CL/F existed between patients with CYP2B6 c.516GT and GG genotypes. Our results indicate that CYP2B6 c.516TT genotype can be used to identify efavirenz poor metabolizers in patients co-treated with rifampin. KeywordsCytochrome P450 2B6; genetic polymorphisms; efavirenz exposure; rifampin Tuberculosis (TB) is the most common complication of human immunodeficiency virus (HIV) infection and is associated with high fatality rates. 1,2 While highly active antiretroviral therapy (HAART) improves survival in co-infected patients, 3-5 potential overlapping drug toxicities, and cytochrome P450 (CYP)-mediated drug-drug interactions constitute major challenges to early initiation of HAART. The magnitude of drug-drug interactions due to rifampin is a major factor in selecting an effective HAART regimen. 6-8 Rifampin is a critical component of TB therapy, 9 but is also a potent inducer of CYP enzyme activity, 10-12 as well as the Pglycoprotein (P-gp) transport system. 13 As a result, the exposure to the HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) is reduced during Currently, it is not known whether CYP induction by rifampin will affect the relationship between CYP2B6 c.516G>T genotype and efavirenz exposure. The reported magnitude of induction of CYP2B6 activity by rifampin in primary human hepatocytes varies. While some authors reported a 7 − 13-fold induction, 10,11 others found only 2.5-fold increase in activity. 12 In one in vivo study, CYP2B6 activity in the presence of rifampin was only 2.1 times that in the absence of rifampin. 23 Co-administration of rifampin with efavirenz 600 mg daily caused a 22% reduction in efavirenz area under the curve (AUC) in HIV/TB co-infected patients, which was overcome by increasing the dose to 800 mg/day. 24 This finding led some experts to recommend an increased efavirenz dose when co-administered with rifampin. 6,7,25 Although an increased efavirenz dose might be appropriate for some persons, it does not take into consideration the variable effect of rifampin on CYP2B6 activity. In the aforementioned pharmacokinetic study, the change in efavirenz AUC with concomitant rifampin ranged from a decrease of 65% to an increase of 37%. 24 Furthermore, vari...

Impact of Pharmacogenetic Markers ofCYP2B6, Clinical Factors, and Drug-Drug Interaction on Efavirenz Concentrations in HIV/Tuberculosis-Coinfected Patients

“…Although the CYP2B6 516GϾT SNP is well known to be useful for predicting plasma efavirenz concentrations, little is known about the plasma efavirenz concentration prediction potential of the other two SNPs. Previous studies in Thais (13,17) and members of other ethnic groups (12,15,24) showed high plasma efavirenz concentrations in HIV-infected patients with the CYP2B6 516TT genotype while receiving rifampin. The frequency of this allele ranges from 15% in Asians up to 50% in Africans (11,15,25).…”

Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-O-Desacetyl-Rifabutin in Healthy Subjects

“…In one study, the change in efavirenz exposure following coadministration with rifampin ranged from a decrease of 65% to an increase of 37% (21), which suggests interindividual differences in enzyme activity. Furthermore, studies have shown that individuals with CYP2B6 516 TT genotypes are at risk of high efavirenz plasma exposures even in the presence of rifampin (20,29). However, efavirenz trough concentrations, the best predictor of virological activity, have been shown to remain above the concentration necessary to suppress HIV in vitro in patients on concomitant rifampin (22).…”

CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India

“…Sex is reported to have a modest influence on the pharmacokinetic profiles of certain antiretroviral drugs, including EFV (6,29). A single nucleotide polymorphism at position 516 on the CYP2B6 gene has been widely reported to influence the pharmacokinetics of EFV (3,14,18,19,31,32,33,38,39). India has a large number of HIV-infected individuals, and access to ART is improving.…”