In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid

Aouri, Manel; Barceló, Catalina; Ternon, Béatrice; Cavassini, Matthias; Anagnostopoulos, Alexia; Yerly, Sabine; Hugues, H.; Vernazza, Pietro; Günthard, Huldrych F.; Buclin, Thierry; Telenti, Amalio; Rotger, Margalida; Décosterd, L.A.

doi:10.1124/dmd.115.065839

Cited by 29 publications

(37 citation statements)

References 29 publications

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“…In vivo studies of efavirenz metabolism have largely reflected in vitro drug metabolism studies, which show that the primary route of efavirenz elimination is through CYP2B6-mediated hydroxylation (18)(19)(20). Of the genetically polymorphic CYPs evaluated in this study, only CYP2B6 metabolizer status was found to be a significant predictor of CL/F.…”

Section: Discussionmentioning

confidence: 85%

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

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

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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

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Section: Discussionmentioning

confidence: 85%

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

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

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“…The potential contribution of efavirenz metabolites to CNS adverse drug reactions of efavirenz needs to be further examined [5]. The majority of efavirenz-induced CNS effects appear early, even after a single dose [6].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms responsible for the CNS toxicity of this drug are yet to be resolved. Efavirenz is metabolised by Cytochrome P450 enzymes and has a number of metabolites [2,[4][5][6]. There are two main metabolites of efavirenz, that is 7-and 8-hydroxefavirenz.…”

Section: Introductionmentioning

confidence: 99%

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Derived wave of gradient driven diffusion's convective flux of efavirenz

Nemaura

2018

J. Phys. Commun.

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“… Introduction : The major efavirenz metabolite, 8-hydroxy-efavirenz, has been reported as plausibly responsible for efavirenz-induced neurotoxic effects [1–3]. Notably, up to 35% of patients on efavirenz suffer from mood changes [4].…”

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confidence: 99%

International Congress of Drug Therapy in HIV Infection 23-26 October 2016, Glasgow, UK

2016

Journal of the International AIDS Society

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Scientific advances over the 35 years since AIDS was first recognized as a new disease, have put us on a clear path towards ending the HIV/AIDS pandemic. Scaling-up access to antiretroviral therapy (ART) and HIV prevention strategies, such as pre-exposure prophylaxis, could dramatically decrease HIV-related deaths and the rate of new HIV infections. Current and future scientific advances, notably in HIV vaccine and cure research, will accelerate this process. Two major directions in HIV vaccine development will be discussed: building on the results from RV 144, the clinical trial in Thailand that resulted in the first modest signal of efficacy for a HIV vaccine; and structure-based immunogen design to elicit broadly neutralizing antibodies. Cure research has accelerated greatly over the past few years in two areas. The first is the prospect of eradicating the HIV reservoir altogether (i.e. a classic cure), which might involve novel latency-reversing and immunotoxic regimens and gene editing techniques to create a host cellular environment that does not allow HIV replication. The second approach involves controlling viral rebound following discontinuation of ART to achieve sustained virological remission employing strategies, such as passive transfer of broadly neutralizing antibodies and therapeutic vaccination. In 2016, the arsenal of scientifically proven interventions available, as well as the hope of others to come, offer unprecedented opportunities to make major gains in the fight against HIV/AIDS. With a major global commitment to implement these scientific advances, the end of the HIV/AIDS pandemic is now achievable.

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In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid

Cited by 29 publications

References 29 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

Derived wave of gradient driven diffusion's convective flux of efavirenz

International Congress of Drug Therapy in HIV Infection 23-26 October 2016, Glasgow, UK

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