Efavirenz–rifampicin interaction: therapeutic drug monitoring to efavirenz dosage optimization in HIV/TBC patients

Cabrera, Salvador; Cordero, Miguel; Iglesias, Alejandro Villamor; Valverde, María P.; Domínguez-Gil, A; García, Maria José

doi:10.1097/qad.0b013e3283189c07

Cited by 11 publications

(7 citation statements)

References 2 publications

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“…However, the higher clearances estimated in this study could be justified in terms of the use of concomitant medication, including the inducer rifampin (rifampicin), a first-line drug in tuberculosis coinfection, which was not recorded in that study, even though this coinfection affected more than 60% of the patients analyzed. Thus, rifampin was probably present in these patients, since this antibiotic has been shown to elicit increases of more than 30% in EFV clearance because of its induction effect on the CYP2B6 and CYP3A4 enzymes (6).…”

Section: Discussionmentioning

confidence: 98%

Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients

Cabrera

Santos

Valverde

et al. 2009

Antimicrob Agents Chemother

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A population pharmacokinetic model for efavirenz has been developed from therapeutic drug monitoring data in human immunodeficiency virus (HIV)-positive patients by using a nonlinear mixed-effect model. The efavirenz plasma concentrations (n ‫؍‬ 375) of 131 patients were analyzed using high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were estimated according to a one-compartment model. The effects of sex, age, total body weight, height, body mass index, and HIV treatment were analyzed. In a subgroup of 32 patients, genetic polymorphisms of the cytochrome P450 2B6 gene (CYP2B6), CYP3A4, and MDR1 were also investigated. Efavirenz oral clearance and the apparent volume of distribution were 9.50 liters/h and 311 liters, respectively. The model included only the effect of CYP2B6 polymorphisms on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%. Patients showing G/T and T/T CYP2B6 polymorphisms exhibited efavirenz clearances that were about 50% and 75% lower than those observed in the patients without these polymorphisms (G/G). Accordingly, to obtain EFV steady-state concentrations within the therapeutic range (1 to 4 mg/liter), it would be advisable to implement a gradual reduction in dose to 400 or 200 mg/day for patients that are intermediate or poor metabolizers, respectively. However, the remaining interindividual variability observed in the pharmacokinetic parameters of the model highlights the need for dose individualization to avoid inadequate exposure to efavirenz and suggests that these recommended doses be used with caution and confirmed by therapeutic drug monitoring and clinical efficacy. The population model can be implemented in pharmacokinetic clinical software for dosage optimization by using the Bayesian approach.

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Section: Discussionmentioning

confidence: 98%

Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients

Cabrera

Santos

Valverde

et al. 2009

Antimicrob Agents Chemother

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“…In addition, a study of 19 Indian patients found EFV CL/F to be slightly higher in the presence of tuberculosis treatment [18]. As a result, various authors have advocated increased doses of EFV in the presence of tuberculosis treatment [19, 20]. Most recently, in silico prediction of the EFV–R interaction utilizing model input data from the literature (including weight and CYP2B6 phenotype) revealed 50 kg as the preferred weight cutoff for EFV dose increment [21].…”

Section: Discussionmentioning

confidence: 99%

The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis

Gengiah

Holford

Botha

et al. 2011

Eur J Clin Pharmacol

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Purpose Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV. Methods Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n=209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks. Results The patients had a median age of 32 (range 19–55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment. Conclusion Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.

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“…Severe CNS toxicities associated with supra-therapeutic efavirenz concentrations has also been reported in individual with CYP2B6 516TT genotype, most of whom benefited from dose reduction to 200 mg daily, while others required discontinuation of efavirenz [32–34]. In contrast, higher efavirenz doses up to 1600 mg daily were required to achieve desired plasma concentrations, as well as virologic suppression in two patients with no identifiable slow-metabolizing phenotype mutation who were also treated rifampin [35]. Taken together, there may be a role for tailored dosing in some patients and this can be improved by pharmacogenetic prediction of individual’s likelihood to have concentrations outside the therapeutic range.…”

Section: Discussionmentioning

confidence: 99%

CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients

Kwara

Lartey

Sagoe

et al. 2009

Aids

107

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Objective UDP-glucuronosyltransferase (UGT) 2B7 was recently identified as the main enzyme mediating efavirenz N-glucuronidation. In this study we determined whether selected UGT2B7 polymorphisms could be used to enhance the prediction of efavirenz plasma concentrations from CYP2B6 and CYP2A6 genotypes. Methods Mid-dose efavirenz plasma concentrations were determined in 94 HIV-infected Ghanaian patients at 2–8 weeks of antiretroviral therapy. CYP2B6 and CYP2A6 genotypes had been previously reported. UGT2B7 exon 2 SNPs c.735A>G (UGT2B7*1c; rs28365062) and c.802C>T (H268Y; UGT2B7*2; rs7439366) were determined by direct sequencing with UGT2B7*1a defined as the reference allele. Relationships between efavirenz plasma concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches. Results The mean (±SD) mid-dose efavirenz plasma concentration was 3218 (±3905) ng/mL with coefficient of variation of 121%. Independent predictors of efavirenz concentration included CYP2B6 c.516TT genotype (4,030 ng/mL increase; 95% CI, 2,882–5,505 ng/mL, P<0.001), UGT2B7*1a carrier status (475 ng/mL increase; 95% CI, 138–899 ng/mL, P=0.004) and CYP2A6*9 and/or *17 carrier status (372 ng/mL increase; 95% CI, 74–742 ng/mL, P=0.013). Overall, CYP2B6 c.516TT genotype, UGT2B7*1a carrier status and CYP2A6*9 or *17 carrier status accounted for 45.2%, 10.1%, and 8.6% of the total variance, respectively. Conclusions Our findings demonstrate independent effects of CYP2A6 and UGT2B7 genetic variation on efavirenz disposition beyond that of the CYP2B6 polymorphisms. The development and testing of a pharmacogenetic algorithm for estimating the appropriate dose of efavirenz should incorporate genotypic data from both the oxidative and glucuronidation pathways.

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Efavirenz–rifampicin interaction: therapeutic drug monitoring to efavirenz dosage optimization in HIV/TBC patients

Cited by 11 publications

References 2 publications

Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients

Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients

The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis

CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients

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