Long-Term Efavirenz Autoinduction and Its Effect on Plasma Exposure in HIV Patients

Ngaimisi, Eliford; Mugusi, Sabina; Minzi, Omary; Sasi, Philip; Riedel, K.; Suda, Akira; Ueda, Nobuhisa; Janabi, Mohammed; Mugusi, Ferdinand; Haefeli, Walter E.; Burhenne, Jürgen; Aklillu, Eleni

doi:10.1038/clpt.2010.172

Cited by 96 publications

(127 citation statements)

References 34 publications

(46 reference statements)

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“…However, patients with a large increase in clearance within the study period showed relatively low steady-state efavirenz concentrations, with some showing subtherapeutic concentrations on day 14. This finding correlates with the finding of Ngaimisi et al of subtherapeutic efavirenz concentrations in Tanzanian patients after 16 weeks of treatment [32], which was related to autoinduction and CYP2B6 polymorphism. This finding suggests that autoinduction exposes a few individuals to a risk of virological failure among populations previously known for high plasma concentrations and adverse effects of efavirenz.…”

Section: Discussionsupporting

confidence: 81%

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

et al. 2011

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BackgroundPharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV-infected Ugandans. MethodsEfavirenz plasma concentrations were obtained for 66 HIV-infected Ugandans initiating efavirenzbased regimens, with blood samples collected at eight time-points over 24 h on day 1 of treatment, and at a further eight time-points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz. ResultsThe mean steady-state minimum plasma concentration (C min ) of efavirenz was 2.9 mg/mL, the mean area under the curve (AUC) was 278.5 h mg/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (C max ) of efavirenz was 44 mg/ mL in 96.6% of participants, while C min was o1 mg/mL in only 4.5%. Overall, 69% of participants experienced adverse central nervous system (CNS) symptoms attributable to efavirenz during the 2-week period, and 95% of these participants were found to have efavirenz plasma concentrations 44 mg/mL, although only half maintained a high concentration until at least 8 h after dosing. ConclusionThe findings of this study show that HIV-infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to C max , regardless of the sampling time.Keywords: autoinduction, efavirenz, pharmacokinetics, Ugandans IntroductionA plasma therapeutic range of 1-4mg/mL has been established for the nonnucleoside reverse transcriptase inhibitor efavirenz [1,2], and great variation in the pharmacokinetics of the drug exists within and between patients, causing variation in drug concentrations [3][4][5][6]. Factors reported to be associated with interpatient variability in efavirenz concentration include gender, ethnicity and genetic polymorphisms [3,4,7,8,36], while autoinduction and adherence [8,9] [3,4,7], while Black patients have been reported to exhibit lower rates of clearance of the drug and hence higher plasma concentrations [10]. A recent study comparing 24-h efavirenz pharmacokinetics between HIV-infected patients and healthy volunteers after a single dose showed patients with HIV/AIDS to have lower efavirenz oral bioavailability compared with healthy volunteers when genetics and gender were controlled for [11].Certain polymorphisms of the gene encoding the major enzyme responsible for efavirenz metabolism, CYP2B6 (an enzyme belonging ...

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Section: Discussionsupporting

confidence: 81%

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

et al. 2011

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“…Our ability to attribute efavirenz concentration changes to a genetic interaction modulating a minor elimination pathway was likely limited by sample size. However, formation of 7-OH efavirenz by CYP2A6 may have a more significant effect on plasma efavirenz concentrations during chronic dosing due to induction of CYP2A6, particularly in those subjects with slow CYP2B6 metabolizer phenotypes who do not exhibit induction of CYP2B6 activity (36)(37)(38). Consequently, some gene-gene interactions may be more prominent as efavirenz is dosed to steady state.…”

Section: Discussionmentioning

confidence: 99%

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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“…Moreover, there may be a genetic susceptibility to the neurotoxic effects of EFV that is related to its rate of metabolism. Extensive EFV metabolizers have been identified that express the ‫1/1ء‬ haplotype of CYP2B6 (Ngaimisi et al, 2010). Thus, a genetic susceptibility in some individuals may exaggerate the neurotoxic effects of EFV because of a rapid metabolism of EFV with accumulations of the 8-OH-EFV metabolite.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Spine Injury Induced by the 8-Hydroxy Metabolite of Efavirenz

Tovar‐y‐Romo

Bumpus

Pomerantz

et al. 2012

J Pharmacol Exp Ther

119

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Despite combination antiretroviral therapies (cARTs), a significant proportion of HIV-infected patients develop HIV-associated neurocognitive disorders (HAND). Ongoing viral replication in the central nervous system (CNS) caused by poor brain penetration of cART may contribute to HAND. However, it has also been proposed that the toxic effects of long-term cART may contribute to HAND. A better understanding of the neurotoxic potential of cART is critically needed in light of the use of CNS-penetrating cARTs to contend with the virus reservoir in the brain. The efavirenz (EFV) metabolites 7-hydroxyefavirenz (7-OH-EFV) and 8-hydroxyefavirenz (8-OH-EFV) were synthesized and purified, and their chemical structures were confirmed by mass spectrometry and NMR. The effects of EFV, 7-OH-EFV, and 8-OH-EFV on calcium, dendritic spine morphology, and survival were determined in primary neurons. EFV, 7-OH-EFV, and 8-OH-EFV each induced neuronal damage in a dose-dependent manner. However, 8-OH-EFV was at least an order of magnitude more toxic than EFV or 7-OH-EFV, inducing considerable damage to dendritic spines at a 10 nM concentration. The 8-OH-EFV metabolite evoked calcium flux in neurons, which was mediated primarily by L-type voltage-operated calcium channels (VOCCs). Blockade of L-type VOCCs protected dendritic spines from 8-OH-EFV-induced damage. Concentrations of EFV and 8-OH-EFV in the cerebral spinal fluid of HIV-infected subjects taking EFV were within the range that damaged neurons in culture. These findings demonstrate that the 8-OH metabolite of EFV is a potent neurotoxin and highlight the importance of directly determining the effects of antiretroviral drugs and drug metabolites on neurons and other brain cells.

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Long-Term Efavirenz Autoinduction and Its Effect on Plasma Exposure in HIV Patients

Cited by 96 publications

References 34 publications

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

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

Dendritic Spine Injury Induced by the 8-Hydroxy Metabolite of Efavirenz

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