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Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB.

ABSTRACT: Objectives:We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB. Methods:Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400?mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4?weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models. Results:We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3?L/h for a typical patient (fat-free mass of 47?kg), resulting in an AUC of 16.5?mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC. Conclusions:Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

SUBMITTER: Naidoo A

PROVIDER: S-EPMC5890691 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB.

Naidoo Anushka A Chirehwa Maxwell M McIlleron Helen H Naidoo Kogieleum K Essack Sabiha S Yende-Zuma Nonhlanhla N Kimba-Phongi Eddy E Adamson John J Govender Katya K Padayatchi Nesri N Denti Paolo P

The Journal of antimicrobial chemotherapy 20170501 5

<h4>Objectives</h4>We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB.<h4>Methods</h4>Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and aga ...[more]

PMID: 28175315

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Project description:BACKGROUND: Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients. METHODS AND FINDINGS: Newly diagnosed treatment naïve TB-HIV co-infected patients (n?=?353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p?=?0.001), higher plasma efavirenz level (p?=?0.009), efavirenz/8-hydroxyefavirenz ratio (p?=?0.036), baseline AST (p?=?0.022), ALT (p?=?0.014), lower hemoglobin (p?=?0.008), and serum albumin (p?=?0.007), NAT2 slow-acetylator genotype (p?=?0.039) and ABCB1 3435TT genotype (p?=?0.001). CONCLUSION: We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.

Dataset Information

Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB.

Publications

Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB.

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