Dataset Information

Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype.

ABSTRACT: OBJECTIVES:An efavirenz-based antiretroviral therapy (ART) regimen is preferred for children more than 3 years of age with tuberculosis. However, rifampin, a key component of antituberculosis therapy, induces CYP2B6. An increased dose of efavirenz is recommended in adults weighing more than 50 kg who require rifampin, but there is scant information in children being treated for tuberculosis. DESIGN:Plasma efavirenz concentrations were compared in 40 children during concomitant treatment for tuberculosis and HIV-1, after stopping rifampicin, and in a control group of children without tuberculosis. Associations with antituberculosis treatment, metabolizer genotype (based on CYP2B6 516G?T, 983T?C, and 15582C?T), weight, and time after dose were evaluated. RESULTS:Compared to children with extensive metabolizer genotypes, efavirenz concentrations were increased 1.42-fold (95% confidence interval, CI 0.94–2.15) and 2.85-fold (95% CI 1.80–4.52) in children with intermediate and slow metabolizer genotypes, respectively. Concomitant antituberculosis treatment increased efavirenz concentrations 1.49-fold (95% CI 1.10–2.01) in children with slow metabolizer genotypes, but did not affect efavirenz concentrations in extensive or intermediate metabolizer genotypes. After adjustment for dose/kg, each kilogram of weight was associated with a 2.8% (95% CI 0.9–4.7) decrease in efavirenz concentrations. Despite higher milligram per kilogram doses, a higher proportion of children in the lowest weight band (10–13.9 kg) had efavirenz concentrations less than 1.0 mg/l than larger children. CONCLUSION:Antituberculosis treatment was not associated with reduced efavirenz concentrations in children, which does not support increased efavirenz doses. Children with slow metabolizer genotype have increased efavirenz concentrations during antituberculosis treatment, likely due to isoniazid inhibiting enzymes involved in accessory metabolic pathways for efavirenz.

SUBMITTER: McIlleron HM

PROVIDER: S-EPMC3879806 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype.

McIlleron Helen M HM Schomaker Michael M Ren Yuan Y Sinxadi Phumla P Nuttall James J C JJ Gous Hermien H Moultrie Harry H Eley Brian B Merry Concepta C Smith Peter P Haas David W DW Maartens Gary G

AIDS (London, England) 20130701 12

<h4>Objectives</h4>An efavirenz-based antiretroviral therapy (ART) regimen is preferred for children more than 3 years of age with tuberculosis. However, rifampin, a key component of antituberculosis therapy, induces CYP2B6. An increased dose of efavirenz is recommended in adults weighing more than 50 kg who require rifampin, but there is scant information in children being treated for tuberculosis.<h4>Design</h4>Plasma efavirenz concentrations were compared in 40 children during concomitant tre ...[more]

PMID: 24180002

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Project description:We compared efavirenz pharmacokinetic (PK) parameters in children with tuberculosis (TB)/human immunodeficiency virus (HIV) coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children 3 to 14 years old with HIV infection, with and without TB, were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization-recommended antituberculosis drug dosages were used in the coinfected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon rank-sum test and within group by signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age Z score, and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz peak concentration (C max), concentration at 12 h (C 12h), C min, and total area under the curve from time 0 to 24 h (AUC0-24h) values were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz C 12h, C min, and AUC0-24h values were lower in TB/HIV-coinfected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC0-24h was higher on than in patients off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children. (The study was registered with ClinicalTrials.gov under registration number NCT01704144.).

Project description:To identify factors associated with variability in rifampin plasma pharmacokinetics and explore the relationship between rifampin pharmacokinetics and change in efavirenz plasma pharmacokinetics with rifampin coadministration.In this randomized, cross-over study, 12 healthy volunteers received either efavirenz 600 mg/day or efavirenz 600 mg with rifampin 600 mg/day for 8 days. After a washout period of at least 2 weeks, subjects crossed over to the alternate 8-day regimen. Samples were obtained for pharmacokinetic assessment on day 8 of each study cycle. Drugs concentrations were determined by a validated high-performance liquid chromatography. Pharmacokinetic parameters were calculated using noncompartmental analysis. Multivariate analysis was used to examine factors associated with rifampin pharmacokinetics. Spearman correlation analysis was used to investigate relationship between rifampin pharmacokinetics and change in efavirenz plasma pharmacokinetics with rifampin coadministration.Of 11 evaluable subjects, the median interquartile range, rifampin peak concentration (Cmax) , area under the concentration-time curve (AUC0-24 hour ), and weight-normalized clearance were 8.9 (7.3-13.8) ?g/ml, 48.8 (29.6-67.4) ?g·h/ml, and 0.19 (0.11-0.29) L/h/kg, respectively. Solute carrier organic anion transporter family member 1B1 (SLCO1B1) c.388A?G and SLCO1B1 c.463C?A polymorphisms jointly had significant effect on rifampin Cmax (R(2) = 0.75). Male sex and SLCO1B1 c.463C?A polymorphism together influenced rifampin AUC0-24 hour (R(2) = 0.52) and weight-normalized clearance (R(2) = 0.65). All four volunteers with rifampin Cmax less than 8 ?g/ml (lower end of the normal range) had c.463CA genotype. Rifampin Cmax and AUC0-24 hour had no significant relationship with the efavirenz AUC0-24 hour ratio or weight-normalized clearance ratio in the presence versus absence of rifampin (p>0.05).Men with the SLCO1B1c.463CA genotype are at increased risk of lower rifampin plasma exposure. However, plasma rifampin concentrations did not correlate with the extent of induction of efavirenz clearance by rifampin during coadministration.

Project description:ObjectivesThe main aim of this study was to investigate the effect of CYP2B6 gene polymorphisms on efavirenz (EFV) plasma concentrations in Han Chinese patients with human immunodeficiency virus (HIV) infection.MethodsIn total, 322 patients were recruited for study. EFV plasma concentrations at steady-state were determined using high-performance liquid chromatography. Genotyping for seven single nucleotide polymorphisms (SNPs), including 171+967C>A, 171+3212C>T, 171+4335T>C, 516G>T, 785A>G, 1295-913G>A, and *1355A>G of CYP2B6, was performed using ligase detection reaction (LDR). SPSS 18.0 and Haploview 4.2 were applied for statistical analyses.ResultsThe average EFV concentration of patients was 2.35±2.09 μg/mL. Overall, 22% patients displayed EFV concentrations out of the therapeutic range of 1-4 μg/mL (13.1% < 1 μg/mL, 9.3% > 4 μg/mL). We observed significant association of 171+967C>A, 171+4335T>C, 516G>T, 785A>G and *1355A>G with high plasma EFV levels (p<.01). The predictive accuracy values of 171+4335CC, 516TT and 785GG for EFV concentrations > 4 μg/mL were 56.7%, 56.7% and 60%, respectively. We observed strong linkage disequilibrium for 171+967C>A, 171+4335T>C, 516G>T and 785A>G, resulting in five haplotypes. The frequencies of the five haplotypes (high to low) were as follows: CCTG (0.328), ACTG (0.280), ACCT (0.189), ATTG (0.186) and ACCG (0.017). The frequency of CCTG (0.524) in patients with EFV plasma concentrations < 1 μg/mL was significantly higher than that in other patient groups, while that of ACCT (0.733) was significantly higher in patients with EFV concentrations > 4 μg/mL, relative to other patient groups. Average EFV concentrations of patients carrying ACTG (1.78 μg/mL), ACCT (7.50 μg/mL), and ATTG (1.92 μg/mL) haplotypes were markedly higher than those of patients carrying the CCTG haplotype. The predictive accuracy of ACCT for EFV > 4 μg/mL was 81%.ConclusionsChinese patients administered standard doses of EFV require therapeutic drug monitoring or personalized medication management. Based on the current findings, we propose that 171+4335T>C, 516G>T, 785A>G and haplotype ACCT may be effectively used as genomic markers for EFV, which should aid in improving the efficacy of EFV-containing treatments and reduce the incidence of adverse reactions.

Project description:BackgroundApproximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults.AimTo investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight.MethodEFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records.ResultsThirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85-19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55-13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level).ConclusionGenetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.

Dataset Information

Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype.

Publications

Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype.

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