Relationship Between Weight, Efavirenz Exposure, and Virologic Suppression in HIV-Infected Patients on Rifampin-Based Tuberculosis Treatment in the AIDS Clinical Trials Group A5221 STRIDE Study

Luetkemeyer, Anne F; Rosenkranz, Susan L.; Lu, Darlene; Marzan, Florence; Ive, Prudence; Hogg, Evelyn; Swindells, Susan; Benson, Constance A.; Grinsztejn, Beatriz; Sanne, Ian; Havlir, Diane V.; Aweeka, Francesca

doi:10.1093/cid/cit246

Cited by 63 publications

(75 citation statements)

References 31 publications

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“…In contrast to the present data showing more marked changes in exposure, the impact of rifampin-based anti-TB drugs on efavirenz exposure in HIV/TB co-infected patients is either very small (<27% in exposure to no effect) or paradoxically increased efavirenz exposure [28–30,41,42]. More importantly, rifampin–efavirenz interactions have no meaningful effect on clinical outcomes of efavirenz [43–45].…”

Section: Discussioncontrasting

confidence: 87%

Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

Cho

Shen

Lemler

et al. 2016

Drug Metabolism and Pharmacokinetics

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The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC–MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ~2.5-fold) and decreased maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–∞) of efavirenz (by ~1.6- and ~2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the Cmax and AUC0–12h of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC0–72h of metabolites to AUC0–72h efavirenz) and the amount of metabolites excreted in urine (Ae0–12hr) (all, p < 0.01). Female subjects had longer elimination half-life (1.6–2.2-fold) and larger weight-adjusted distribution volume (1.6– 1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme.

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Section: Discussioncontrasting

confidence: 87%

Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

Cho

Shen

Lemler

et al. 2016

Drug Metabolism and Pharmacokinetics

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“…36 A recent pharmacokinetic evaluation of the STRIDE study found that co-administration of efavirenz and rifampin was associated with a trend towards higher, rather than lower, efavirenz C min compared to efavirenz alone. 37 Those weighing ≥60 kg had lower efavirenz C min than those < 60 kg, but did not have lower viral suppression rates.…”

Section: Diagnosis Of Active Tuberculosismentioning

confidence: 91%

Update on Opportunistic Infections in the Era of Effective Antiretroviral Therapy

Zanoni¹,

Gandhi²

2014

Infectious Disease Clinics of North America

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“…2,3,18,20 However, a wide degree of interindividual variability in EFV plasma concentrations has been observed, thus making EFV weight-based dosing somewhat unreliable. 21,22 Efavirenz is mainly metabolized through hepatic CYP450 CYP3A4 and 2B6, and recent studies have shown that some ethnicities may be predisposed to slow-metabolizing genetic polymorphisms of CYP2B6 and may not require the dose increase. 2,23 Furthermore, EFV 800 mg daily has not been consistently shown to result in superior virologic suppression and increased concentrations have been associated with central nervous system toxicities.…”

Section: Discussionmentioning

confidence: 99%

The Use of Therapeutic Drug Monitoring in Complex Antituberculous and Antiretroviral Drug Dosing in HIV/Tuberculosis-Coinfected Patients

Newman

Foisy

Ahmed

2014

J Int Assoc Provid AIDS Care

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Over the 12-month course of TB therapy, drugs that required increased doses due to incomplete and/or delayed absorption were rifampin (1500 mg), moxifloxacin (800 mg), and ethambutol (1600 mg). Higher drug doses were well tolerated until the end of treatment. Due to delayed/incomplete drug absorption and weight gain during therapy, higher antituberculous doses may be required in patients coinfected with HIV/TB. A daily dose of efavirenz 800 mg was well tolerated in both patients (weight over 70 kg). Managing patients coinfected with HIV/TB is complex, and, therefore, TDM of drug concentrations can help guide clinical decision making.

show abstract

Relationship Between Weight, Efavirenz Exposure, and Virologic Suppression in HIV-Infected Patients on Rifampin-Based Tuberculosis Treatment in the AIDS Clinical Trials Group A5221 STRIDE Study

Cited by 63 publications

References 31 publications

Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

Update on Opportunistic Infections in the Era of Effective Antiretroviral Therapy

The Use of Therapeutic Drug Monitoring in Complex Antituberculous and Antiretroviral Drug Dosing in HIV/Tuberculosis-Coinfected Patients

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