Dataset Information

Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy.

ABSTRACT: Some individuals have higher efavirenz plasma concentrations during rifampin-containing tuberculosis (TB) therapy, contrary to the expected induction effect of rifampin. Among HIV-infected patients without (n = 38) and with TB on rifampin-containing therapy (n = 18), we tested the hypothesis that drug-gene interaction may explain the highly variable drug interactions. Two-way analysis of variance revealed a significant interaction between CYP2B6 516G?T polymorphism and rifampin-containing therapy, suggesting that efavirenz dose adjustment may need to be individualized on the basis of the patient's genotype.

SUBMITTER: Kwara A

PROVIDER: S-EPMC6170200 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy.

Kwara Awewura A Lartey Margaret M Sagoe Kwamena W KW Court Michael H MH

AIDS (London, England) 20110101 3

Some individuals have higher efavirenz plasma concentrations during rifampin-containing tuberculosis (TB) therapy, contrary to the expected induction effect of rifampin. Among HIV-infected patients without (n = 38) and with TB on rifampin-containing therapy (n = 18), we tested the hypothesis that drug-gene interaction may explain the highly variable drug interactions. Two-way analysis of variance revealed a significant interaction between CYP2B6 516G→T polymorphism and rifampin-containing therap ...[more]

PMID: 21150552

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Project description:This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of rifampin and isoniazid when coadministered with nevirapine or efavirenz were not altered to a clinically significant extent in these severely immunosuppressed HIV-infected patients. Patients experienced favorable clinical outcomes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00495326.).

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.

Dataset Information

Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy.

Publications

Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy.

Similar Datasets

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