<i>CYP2B6</i>
            Genotype, but not Rifampicin-Based Anti-TB Cotreatments, Explains Variability in Long-Term Efavirenz Plasma Exposure

Mukonzo, Jackson; Nanzigu, Sarah; Waako, Paul; Ogwal-Okeng, Jasper; Gustafson, L.; Aklillu, Eleni

doi:10.2217/pgs.14.73

Cited by 17 publications

(25 citation statements)

References 44 publications

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“…Semvua et al reported a similar outcome in Tanzanian patients, although C max , C min , and AUC 0–24 were slightly but insignificantly lower during RIF cotreatment . No effects of RIF coadministration on plasma concentrations of EFV at C mid‐dose or C min were reported in Cambodian, South African, Thai, Ugandan, and Tanzanian patients . However, our finding is in disagreement with a recent report by Cho et al, who demonstrated a decrease in EFV exposure parameters with a corresponding increase in 8‐OH‐EFV on a single dose of EFV after 10 days of RIF pretreatment in healthy volunteers, and with an earlier report by López‐Cortés et al, who showed significant decreases in C max , C min , and AUC 0–24 in the presence of RIF coadministration…”

Section: Discussioncontrasting

confidence: 78%

Long‐Term Effect of Rifampicin‐Based Anti‐TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8‐Hydroxy‐Efavirenz in Ethiopian Patients

Habtewold

Aklillu

Makonnen

et al. 2016

The Journal of Clinical Pharma

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We compared the pharmacokinetic (PK) exposure parameters of efavirenz (EFV) and its major inactive metabolite, 8-hydroxy-efavirenz (8-OH-EFV), in an open-label, single-sequence, and parallel design of HIV-infected and tuberculosis (TB)-HIV-coinfected Ethiopian patients in the HIV-TB Pharmagene study with 20 and 33 patients, respectively. Both treatment groups underwent PK sampling following oral 600 mg EFV in week 16 of initiating EFV-based combination antiretroviral therapy. The TB-HIV-coinfected group repeated the PK sampling 8 weeks after stopping rifampin (RIF)-based anti-TB treatment. Between-treatment group analysis indicated no significant effect of RIF-based anti-TB cotreatment on PK exposure parameters of EFV, nor was there a significant effect after controlling for sex or CYP2B6 genotype. However, RIF-based therapy in TB-HIV-coinfected patients had significantly increased 8-OH-EFV PK exposure measures and metabolic ratio relative to HIV-only patients, AUC greater by 79%. The effect was more prominent in women and CYP2B6*6 carriers in within-sex and CYP2B6 genotype comparisons. Within-subject comparisons for AUC and C when "on" and "off" RIF-based anti-TB cotreatment showed geometric mean ratios (90% confidence intervals) of 100.5% (98.7%-102.3%) and 100.2% (98.1%-102.4%), respectively, for EFV and 98.6% (95.5%-101.7%-) and 97.6% (92.2%-103.0%), respectively, for 8-OH-EFV. We report no significant influence of RIF-based anti-TB cotherapy on the EFV PK exposure measures. The study also calls for caution related to higher exposure to 8-OH-EFV during simultaneous coadministration of EFV and RIF-based anti-TB regimens, which may be associated with neurotoxicity, particularly in female patients and CYP2B6*6 carriers.

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Section: Discussioncontrasting

confidence: 78%

Long‐Term Effect of Rifampicin‐Based Anti‐TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8‐Hydroxy‐Efavirenz in Ethiopian Patients

Habtewold

Aklillu

Makonnen

et al. 2016

The Journal of Clinical Pharma

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“…Contradictory reports exist in the literature, though recent studies, including our noncompartmental PK and PK-pharmacodynamics (PD) relationship analyses reported on EFV using the same data, suggest the absence of a significant effect of a RIF-based anti-TB regimen (13,(31)(32)(33). The covariate analysis in the present study confirmed the absence of the effect of a RIF-based anti-TB regimen on the disposition of EFV and 8OHEFV.…”

Section: Discussionsupporting

confidence: 78%

“…PK models describing the disposition of efavirenz in plasma have been reported previously (3,(10)(11)(12)(13). A single study reported a PK model comprising both the parent drug (EFV) and the metabolite (8OHEFV) in plasma after a single dose that was lower than the recommended dose of efavirenz in 17 healthy Korean male subjects (14).…”

mentioning

confidence: 99%

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Habtewold

Aklillu

Makonnen

et al. 2017

Antimicrob Agents Chemother

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The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 Ϯ 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers CYP2B6*6, CYP3A5*3, CYP3A5*6, UGT2B7*2, ABCB1 (3435C¡T, 3842A¡G), OATP1B1*1B, and OATP1B1*5, the presence of a rifampin-based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (K a ) and absorption lag time (A lag ) (K a ϭ 0.2 h Ϫ1 ; A lag ϭ 0.83 h; central compartment clearance [CL c /F] for CYP2B6*1/*1 ϭ 18 liters/h, for CYP2B6*1/*6 ϭ 14 liters/h, and for CYP2B6*6/*6 ϭ 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CL p /F ϭ 32 liters/h), followed by capacity-limited return (V max ϭ 4,400 ng/ml/h; K m ϭ 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except for CYP2B6*6 genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs. CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.KEYWORDS efavirenz, 8-hydroxy-efavirenz, peripheral blood mononuclear cells, population pharmacokinetics E favirenz (EFV)-based antiretroviral therapy remains the preferred first-line treatment option in important international guidelines, including those of the World Health Organization (1). EFV displays a wide between-patient pharmacokinetic (PK) variability (2, 3). This is ascribed partially to genetic variation of the CYP2B6 enzyme, which is primarily responsible for the metabolism of efavirenz to 8-hydroxy-efavirenz (8OHEFV) (4, 5). Efavirenz is described to have a narrow safety margin (6-8). In addition, a couple

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“…[19][20][21][22][23][24] Moreover, the genes coding for theses enzymes and transporter proteins are genetically polymorphic displaying wide interethnic and interindividual variations in EFV, NVP or lumefantrine disposition. 23,[25][26][27][28][29] Concomitant ART and antimalarial drugs treatment is marred by drug-drug interactions involving inhibition and/or induction of drug-metabolizing enzymes or transporter proteins, whose extent may further be influenced by pharmacogenetics variations. As HIV treatment is life-long, long-term CYP3A induction by chronic use of EFV in HIV patients 22,30 may lower the plasma exposure of antimalarial drugs such as lumefantrine to cause treatment failure or drug resistance.…”

Section: Introductionmentioning

confidence: 99%

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

et al. 2015

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We investigated the influence of efavirenz (EFV)- or nevirapine (NVP)-based antiretroviral therapy (ART) on lumefantrine plasma exposure in HIV-malaria-coinfected patients and implication of pharmacogenetic variations. A total of 269 HIV patients with uncomplicated falciparum malaria on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) or not receiving ART (control-arm) were enrolled and treated with artemether-lumefantrine. Day-7 lumefantrine, baseline EFV and NVP plasma concentrations, and CYP2B6*6,*18, CYP3A4*1B, CYP3A5*3,*6,*7, ABCB1 c.3435C>T and ABCB1 c.4036A>G genotypes were determined. The median day-7 lumefantrine plasma concentration was significantly lower in the EFV-arm compared with that in NVP- and control-arm. High EFV plasma concentrations and CYP2B6*6/*6 genotype significantly correlated with low lumefantrine plasma concentrations and high rate of recurrent parasitemia. No significant effect of NVP-based ART on lumefantrine exposure was observed. In conclusion, owing to long-term CYP3A induction, EFV-based ART cotreatment significantly reduces lumefantrine plasma exposure leading to poor malaria treatment response, which is more pronounced in CYP2B6 slow metabolizers.

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CYP2B6 Genotype, but not Rifampicin-Based Anti-TB Cotreatments, Explains Variability in Long-Term Efavirenz Plasma Exposure

Abstract: Plasma efavirenz exposure is mainly influenced by CYP2B6 genotype, but not by rifampicin cotreatment. Therefore, no efavirenz dosage adjustment during rifampicin cotreatment is required in Ugandans.

Cited by 17 publications

References 44 publications

Long‐Term Effect of Rifampicin‐Based Anti‐TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8‐Hydroxy‐Efavirenz in Ethiopian Patients

Long‐Term Effect of Rifampicin‐Based Anti‐TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8‐Hydroxy‐Efavirenz in Ethiopian Patients

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

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