Body Weight Cutoff for Daily Dosage of Efavirenz and 60-Week Efficacy of Efavirenz-Based Regimen in Human Immunodeficiency Virus and Tuberculosis Coinfected Patients Receiving Rifampin

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...

Section: Discussionsupporting

confidence: 77%

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

“…By multivariate analyses, efavirenz concentrations persistently decreased 0.7 mg/liter (coefficients ϭ Ϫ0.07) for every 10-kg increase in patient body weight. A cross-sectional study from the Liverpool therapeutic drug monitoring registry and a study in Thais showed that body weight was an independent predictive factor for the plasma efavirenz concentration (20,21), although some previous studies were not able to demonstrate this effect (22,23). Moreover, patients' body weights increased over time while on treatment.…”

Section: Discussionmentioning

confidence: 99%

Impact of Pharmacogenetic Markers ofCYP2B6, Clinical Factors, and Drug-Drug Interaction on Efavirenz Concentrations in HIV/Tuberculosis-Coinfected Patients

Manosuthi

Sukasem

Lueangniyomkul

et al. 2013

Self Cite

bComprehensive information on the effects of cytochrome P450 2B6 (CYP2B6) polymorphisms, clinical factors, and drug-drug interactions on efavirenz concentrations in HIV/tuberculosis-coinfected (HIV/TB) patients is unavailable. A total of 139 HIV/TB adults, 101 of whom received a rifampin-containing anti-TB regimen, were prospectively enrolled to receive efavirenz (600 mg)/ tenofovir/lamivudine. Nine single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Plasma efavirenz concentrations were measured at 12 weeks. The median (interquartile range [IQR]) efavirenz concentration was 2.3 (1.4 to 3.9) mg/liter. The SNPs (frequencies of heterozygous and homozygous mutants) were 64C>T (10% and 1%), 499C>G (0% and 0%), 516G>T (47% and 8%), 785A>G (54% and 10%), 1375A>G (0% and 0%), 1459C>T (3% and 0%), 3003C>T (44% and 27%), 18492T>C (39% and 6%), and 21563C>T (57% and 5%). The four most frequent CYP2B6 haplotypes identified were *1/*6 (41%), *1/*1 (35%), *1/*2 (7%), and *6/*6 (7%). The heterozygous/homozygous mutation associated with low efavirenz concentrations was 18492T>C (P < 0.001), and those associated with high efavirenz concentrations were 516G>T, 785A>G, and 21563C>T (all P < 0.05). Haplotype *1/*1 was associated with low efavirenz concentrations, and *6/*6, *1/*6, and *5/6 were associated with high efavirenz concentrations. As shown by multivariate analysis, low efavirenz concentrations were significantly associated with the *1/*1 haplotype (beta ‫؍‬ ؊1.084, P ‫؍‬ 0.027) and high body weight (beta ‫؍‬ ؊0.076, P ‫؍‬ 0.002). In conclusion, pharmacogenetic markers of CYP2B6 have the greatest impact with respect to inducing low plasma efavirenz concentrations in HIV/TB Thai patients.

“…Substantial interpatient variability of efavirenz concentrations with a Ͼ100% coefficient of variation after fixed standard doses is well known. Previous reports in Thais demonstrated wide ranges of interpatient variability, ranging from 77% to 136% (6,24). This can be explained by the fact that other SNPs were excluded before the final analysis, and only the patients who carried CYP2B6 haplotype *1/*1 were enrolled, suggesting that other factors that potentially influence efavirenz concentration were minimized, even if variation is usually even greater when efavirenz was coadministered with rifampin (25,26).…”

Section: Discussionmentioning

confidence: 99%

CYP2B6 18492T→C Polymorphism Compromises Efavirenz Concentration in Coinfected HIV and Tuberculosis Patients Carrying CYP2B6 Haplotype 1/1

Manosuthi

Sukasem

Thongyen

et al. 2014

Self Cite

Data regarding the effect of the CYP2B6 18492T¡C polymorphism on plasma efavirenz concentrations and 96-week virologic responses in patients coinfected with HIV and tuberculosis (TB) are still unavailable. A total of 139 antiretroviral-naive HIVinfected adults with active TB were prospectively enrolled to receive efavirenz 600 mg-tenofovir 300 mg-lamivudine 300 mg. Eight single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Seven SNPs, including 64C¡T, 499C¡G, 516G¡T, 785A¡G, 1375A¡G, 1459C¡T, and 21563C¡T, were included for CYP2B6 haplotype determination. The CYP2B6 18492T¡C polymorphism was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after antiretroviral therapy, plasma efavirenz concentrations at 12 h after dosing were measured. Plasma HIV RNA was monitored every 12 weeks for 96 weeks. Of 48 patients {body weight [mean ؎ standard deviation (SD)], 56 ؎ 10 kg}, 77% received a rifampin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of the wild type (18492TT) and the heterozygous (18492TC) and homozygous (18492CC) mutants of the CYP2B6 18492T¡C polymorphism were 39%, 42%, and 19%, respectively. At 12 weeks, mean (؎SD) efavirenz concentrations of patients who carried the 18492TT, 18492TC, and 18492CC mutants were 2.8 ؎ 1.6, 1.7 ؎ 0.9, and 1.4 ؎ 0.5 mg/liter, respectively (P ‫؍‬ 0.005). At 24 weeks, the efavirenz concentrations of the corresponding groups were 2.4 ؎ 0.8, 1.7 ؎ 0.8, and 1.2 ؎ 0.4 mg/liter, respectively (P ‫؍‬ 0.003). A low efavirenz concentration was independently associated with 18492T¡C (␤ ‫؍‬ ؊0.937, P ‫؍‬ 0.004) and high body weight (␤ ‫؍‬ ؊0.032, P ‫؍‬ 0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying the 18492TT, 18492TC, and 18492CC mutants, respectively, had plasma HIV RNA levels of >40 copies/ml and developed efavirenz-associated mutations (P ‫؍‬ 0.254). In summary, the CYP2B6 18492T¡C polymorphism compromises efavirenz concentrations in patients who carry CYP2B6 haplotype *1/*1 and are coinfected with HIV and tuberculosis.