Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir-ritonavir-based antiretroviral therapyReport as inadecuate




Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir-ritonavir-based antiretroviral therapy - Download this document for free, or read online. Document in PDF available to download.

BMC Pharmacology and Toxicology

, 15:61

Clinical pharmacology

Abstract

BackgroundPharmacokinetic interactions between rifampicin and protease inhibitors PIs complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin 150 mg daily in combination with boosted lopinavir LPV-r, than the previous dose of rifabutin 150 mg three times weekly {tiw}. But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV-r. Sub-optimal dosing can lead to acquired rifamycin resistance ARR. The plasma concentration of 25-O-desacetylrifabutin d-RBT, the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity.

Methods and resultsSixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy initially pyrazinamide, isoniazid and ethambutol then only isoniazid, and were then randomized to receive isoniazid and LPV-r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0–48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio 90% CI for AUC0–48 and Cmax was 0.6 0.5-0.7 and 0.5 0.4-0.6 for RBT 150 mg tiw compared with RBT 300 mg and 0.4 0.4-0.4 and 0.5 0.5-0.6 for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 μg.h-mL, which has previously been associated with acquired rifamycin resistance ARR. Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis grade 4, occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia asymptomatic was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations.

ConclusionsA daily 150 mg dose of rifabutin in combination with LPV-r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR.

Trial registrationClinicalTrials.gov Identifier: NCT00640887

KeywordsRifabutin Pharmacokinetics Lopinavir Tuberculosis HIV DDI Randomized Clinical trial Neutropenia Uveitis Electronic supplementary materialThe online version of this article doi:10.1186-2050-6511-15-61 contains supplementary material, which is available to authorized users.

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Author: Suhashni Naiker - Cathy Connolly - Lubbe Wiesner - Tracey Kellerman - Tarylee Reddy - Anthony Harries - Helen McIlleron - C

Source: https://link.springer.com/



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