Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all

Brennan-Benson, Paul; Lyus, Richard; Harrison, Thomas S.; Pakianathan, Mark; Macallan, Derek C.

doi:10.1097/01.aids.0000183519.45137.a6

Cited by 58 publications

(58 citation statements)

References 5 publications

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“…Moreover, the use of lamivudine and lopinavir has been shown to be associated with insomnia [24]. However, efavirenz-based therapies have been associated with sleep disorders among these groups of patients in similar studies [8,9,12,25]. In conformity with similar studies [12,25,26], lower CD4 count levels were associated with the presence of sleep disorders.…”

Section: Discussionmentioning

confidence: 54%

“…Efavirenz is associated with decrease in sleep duration which usually resolves within the first week of treatment [6,7]. Higher rates of neuropsychiatric disorders in patients of African origin have been reported to be linked with the increased serum levels of efavirenz [8,9]. It is postulated that the defective CYP2B6 G516T variant allele, which is common in African population, impairs the efavirenz metabolism, thus increasing the efavirenz plasma concentrations, thereby leading to toxicity [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Predictors of Sleep Disorders among HIV Out-Patients in a Tertiary Hospital

Bisong¹,

Williams²,

Okpa³

et al. 2017

Recent Advances in Biology and Medicine

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Human immunodeficiency virus (HIV)-infected individuals have been shown to have a high prevalence of sleep disturbances. Both the effects of the virus and the antiretroviral drugs may cause sleep disturbances. We sought to determine the prevalence and predictors of sleep disorders among HIV seropositive adult subjects presenting at an outpatient hospital setting. One hundred and fifty six subjects were recruited for the study by using a sleep disorder screening questionnaire. The mean ages of the participants were 38.7 6 9.23 and 39.5 6 9.23 for those with and those without sleep disorder, respectively. The prevalence rate of sleep disorders was 46.2%. Elevated systolic blood pressure, lower CD4 count levels, and being on the highly active antiretroviral therapy combination TDF/3TC/ATZ/lpvr were associated with sleep disorders. The high prevalence rate observed necessitates routine screening for sleep disorders among HIV/AIDs patients.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Predictors of Sleep Disorders among HIV Out-Patients in a Tertiary Hospital

Bisong¹,

Williams²,

Okpa³

et al. 2017

Recent Advances in Biology and Medicine

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“…The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95% confidence interval [13][14][15][16][17][18][19] in efavirenz area under the concentration-time curve, of the same magnitude as what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight.…”

Section: Resultsmentioning

confidence: 99%

In silico prediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotype

Rekić

Röshammar

Mukonzo

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rifampicin is known to reduce the exposure of efavirenz. Despite lack of adequate clinical support, most guidelines recommend an increased efavirenz dose in patients treated with both drugs, although some propose an increase only in patients weighing over 50 kg. WHAT THIS STUDY ADDS • An example of utilization of in vitro data to predict in vivo consequences of metabolic drug–drug interactions, suggesting answers to specific questions difficult to study in patients. Here the efavirenz–rifampicin interaction was simulated with the specific question of whether or not to increase the efavirenz dose based on bodyweight. • The results from this simulation suggest that increasing the efavirenz dose may be appropriate only in patients with bodyweights over 50 kg. AIMS This study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight‐based dosage recommendations used to counteract the rifampicin–efavirenz interaction. METHODS Efavirenz pharmacokinetics were simulated using a physiologically based pharmacokinetic model implemented in the Simcyp™ population‐based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype. RESULTS Apart from the absorption phase, the simulation model predicted efavirenz concentration–time profiles reasonably well, with close agreement with clinical data. The simulated effects of rifampicin co‐administration on efavirenz treatment showed only a minor decrease of 16% (95% confidence interval 13–19) in efavirenz area under the concentration–time curve, of the same magnitude as what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status. CONCLUSIONS Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut‐off for efavirenz dose increment when co‐treating with rifampicin.

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“…Many patients achieve adequate efficacy and tolerability with 600 mg or 800 mg efavirenz daily during coadministration with rifampin (3,23,27). However, 800 mg efavirenz daily was associated with a high frequency of central nervous system (CNS) and hepatic toxicities associated with supratherapeutic plasma concentrations in black native Africans (3).…”

Section: Discussionmentioning

confidence: 99%

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

Kwara

Tashima

Dumond

et al. 2011

Antimicrob Agents Chemother

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Efavirenz-based antiretroviral regimen is preferred during rifampin-containing tuberculosis therapy. However, current pharmacokinetic data are insufficient to guide optimized concurrent dosing. This study aimed to better characterize the effects of rifampin on efavirenz pharmacokinetics. Subjects were randomized to receive 600 mg efavirenz/day or 600 mg efavirenz with 600 mg rifampin/day for 8 days, with plasma samples collected for pharmacokinetic analysis over 24 h on day 8. Treatments were then crossed over after at least a 2-week washout period, and procedures were repeated. Efavirenz concentrations were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were estimated by noncompartmental analysis. Efavirenz pharmacokinetic differences between treatment periods were evaluated by paired t test. The coefficients of variation in efavirenz plasma AUC 0-24 (area under the concentration-time curve from 0 to 24 h) were 50% and 56% in the absence and presence of rifampin, respectively. Of the 11 evaluable subjects (6 white, 5 black; 6 women, 5 men), the geometric mean AUC 0-24 ratio on/off rifampin (90% confidence interval) was 0.82 (0.72, 0.92), with individual AUC 0-24 ratios varying from 0.55 to 1.18. Five subjects had a 24-hour efavirenz concentration (C 24 ) of <1,000 ng/ml on rifampin. They were more likely to have received a lower dose in milligrams/kilogram of body weight and to have lower efavirenz AUC 0-24 values in the basal state. Although rifampin resulted in a modest reduction in efavirenz plasma exposure in subjects as a whole, there was high variability in responses between subjects, suggesting that efavirenz dose adjustment with rifampin may need to be individualized. Body weight and genetic factors will be important covariates in dosing algorithms.Efavirenz is an essential component of preferred antiretroviral regimens in treatment of human immunodeficiency virus (HIV) infection in patients coinfected with tuberculosis (TB) (6,32,33). The standard adult dose of 600 mg daily is associated with considerable interindividual variability in plasma concentrations and clinical effects (10,28,38). There is even greater variability in efavirenz concentrations during coadministration with rifampin or rifampin-containing TB therapy (2,13,29). Efavirenz is primarily metabolized by hepatic CYP2B6, with some contributions from CYP3A4/5 (42), CYP2A6 (30), and UGT2B7 enzymes (1). Rifampin was shown to be a potent inducer of CYP2B6 activity when bupropion was used as a probe of enzyme activity (22). Among healthy volunteers, rifampin caused 26% and 20% reductions in mean efavirenz area under the curve (AUC) and maximum concentration (C max ), respectively (2). Among HIV-TB-coinfected patients, mean reductions of 24% and 25% in efavirenz AUC and C max , respectively, were reported with rifampin coadministration. In the above-mentioned studies, some subjects had higher efavirenz plasma exposure with rifampin (compared with that when off rifampin), suggesting a lack of a signif...

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Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all

Cited by 58 publications

References 5 publications

Predictors of Sleep Disorders among HIV Out-Patients in a Tertiary Hospital

Predictors of Sleep Disorders among HIV Out-Patients in a Tertiary Hospital

In silico prediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotype

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

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