Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes

Haas, David W.; Kwara, Awewura; Richardson, Danielle; Baker, Paxton; Papageorgiou, Ioannis; Acosta, Edward P.; Morse, Gene D.; Court, Michael H.

doi:10.1093/jac/dku110

Cited by 49 publications

(61 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is expected that the CYP2B6 variants evaluated in this study account for the majority of the influence of CYP2B6 genetic variability on efavirenz concentrations in the population studied, given the relatively low allelic frequency and/or minor effects of additional variants (28,35). In addition to CYP2B6, CYP2A6 polymorphisms have been shown to be associated with efavirenz CL/F, efavirenz concentrations, or 7-OH efavirenz concentrations (25,29,30). In these studies, the relative influence of the CYP2A6 genotypes on efavirenz PK was more prominent in CYP2B6 slow metabolizers, suggesting that the minor elimination pathway of 7-hydroxylation mediated by CYP2A6 may play an increased role in subjects with low CYP2B6 activity (20).…”

Section: Discussionmentioning

confidence: 91%

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6. While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero-and firstorder processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.) KEYWORDS body composition, cytochrome P450 2B6 (CYP2B6), efavirenz, population pharmacokinetics E favirenz is a nonnucleoside reverse transcriptase inhibitor that is used in combination with nucleoside/nucleotide reverse transcriptase inhibitors to treat HIVinfected individuals older than 3 years who are naive to antiretroviral drugs. Due to its proven efficacy and low cost relative to newer antiretrovirals, efavirenz-based therapy remains the preferred first-line regimen in many low-income nations and is consequently one of the most commonly prescribed antiretroviral drugs (1). Efavirenz pharmacokinetics (PK) is characterized by large interindividual variability in plasma concentrations following a single dose (2, 3) and during chronic administration (4), which has important clinical implications. During the induction phase, efavirenz exposure is associated with central nervous system and psychiatric adverse events, liver enzyme elevation, and rash, among others (5, 6). This may result in increasing rates of

show abstract

Section: Discussionmentioning

confidence: 91%

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…This was confirmed in a separate genomewide association study (GWAS) in 856 individuals that found no association between rs28399433 and estimated plasma trough concentrations of EFV [39]. However, when investigating only individuals with a CYP2B6 slow metabolizer genotype (defined by genotypes 516TT, or 516T/983C or 983CC of two SNPs rs3745274 and rs28399499) a significant association was observed between the CYP2A6 rs28399433 AC genotype and higher EFV plasma concentrations (as compared to AA genotype) [52]. The clinical relevance of this SNP on EFV treatment is unclear since no association with immunological failure, virologic response, or CNS toxicity has been reported (Table 2).…”

Section: Pharmacogeneticsmentioning

confidence: 82%

PharmGKB summary

McDonagh¹,

Lau

Alvarellos³

et al. 2015

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

“…CYP2B6 516G > T, 983T > C, 785A > G and 21563C > T SNPs have been associated with greater efavirenz plasma exposure and the development of more severe central nervous system (CNS) effects in different HIV-infected populations, including African and Thai patients [39][40][41][42][43][44][45][46] . Likewise, increased efavirenz concentrations were associated with CYP2A6 -48T > G and with GG homozygosity for UGT2B7 735, a SNP of the microsomal enzyme uridine 5'-diphospho-glucuronosyltransferase (UGT), in Black and White, but not in Hispanic individuals from the United States [47] . Also, CYP2B6 *6/*6 and *6/*26 carriers have been found to be associated with extremely high plasma concentrations of efavirenz in Japanese patients receiving standard doses of the drug [48] .…”

Section: Nervous System Side Effectsmentioning

confidence: 99%

Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics

Asensi¹

2015

WJV

View full text Add to dashboard Cite

Pharmacogenetics refers to the effect of single nucle otide polymorphisms (SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction (HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus (HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5 , APOB , APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1 (MDR1) 3435C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity. genotyping to prevent the abacavir-associated hypersensitivity reaction. Diverse other single nucleotide polymorphisms have been described as related to certain pharmacokinetic characteristics and adverse effects of antiretroviral drugs. In this Editorial we summarize the current knowledge on this rapidly evolving field.Asensi V, Collazos J, Valle-Garay E. Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual?

show abstract

Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes

Abstract: Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.

Cited by 49 publications

References 45 publications

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

PharmGKB summary

Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics

Contact Info

Product

Resources

About