Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy

 

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dc.contributor.author Naiker, Suhashni
dc.contributor.author Connolly, Cathy
dc.contributor.author Wiesner, Lubbe
dc.contributor.author Kellerman, Tracey
dc.contributor.author Reddy, Tarylee
dc.contributor.author Harries, Anthony
dc.contributor.author McIlleron, Helen
dc.contributor.author Lienhardt, Christian
dc.contributor.author Pym, Alexander
dc.date.accessioned 2015-07-30T03:59:04Z
dc.date.available 2015-07-30T03:59:04Z
dc.date.issued 2014-11-19
dc.identifier.citation Naiker, S., Connolly, C., Wiesner, L., Kellerman, T., Reddy, T., Harries, A., ... & Pym, A. (2014). Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV-infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacology and Toxicology, 15(1), 61.
dc.identifier.uri http://hdl.handle.net/11427/13604
dc.identifier.uri http://dx.doi.org/10.1186/2050-6511-15-61
dc.description.abstract Abstract Background Pharmacokinetic 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 results Sixteen 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. Conclusions A 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 registration ClinicalTrials.gov Identifier: NCT00640887
dc.rights This is an Open Access article distributed under the terms of the Creative Commons Attribution License *
dc.rights.uri http://creativecommons.org/licenses/by/2.0 *
dc.source BMC Pharmacology and Toxicology en_ZA
dc.source.uri http://www.biomedcentral.com/bmcpharmacoltoxicol/
dc.subject.other Rifabutin en_ZA
dc.subject.other Pharmacokinetics en_ZA
dc.subject.other Lopinavir en_ZA
dc.subject.other Tuberculosis en_ZA
dc.subject.other HIV en_ZA
dc.subject.other DDI en_ZA
dc.subject.other Randomized en_ZA
dc.subject.other Clinical trial en_ZA
dc.subject.other Neutropenia en_ZA
dc.subject.other Uveitis en_ZA
dc.title Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy
dc.type Journal Article en_ZA
dc.date.updated 2015-01-15T17:59:11Z
dc.language.rfc3066 en
dc.rights.holder Naiker et al.; licensee BioMed Central Ltd.
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Division of Clinical Pharmacology en_ZA
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uct.type.filetype Text
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dc.identifier.apacitation Naiker, S., Connolly, C., Wiesner, L., Kellerman, T., Reddy, T., Harries, A., ... Pym, A. (2014). Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy. <i>BMC Pharmacology and Toxicology</i>, http://hdl.handle.net/11427/13604 en_ZA
dc.identifier.chicagocitation Naiker, Suhashni, Cathy Connolly, Lubbe Wiesner, Tracey Kellerman, Tarylee Reddy, Anthony Harries, Helen McIlleron, Christian Lienhardt, and Alexander Pym "Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy." <i>BMC Pharmacology and Toxicology</i> (2014) http://hdl.handle.net/11427/13604 en_ZA
dc.identifier.vancouvercitation Naiker S, Connolly C, Wiesner L, Kellerman T, Reddy T, Harries A, et al. Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacology and Toxicology. 2014; http://hdl.handle.net/11427/13604. en_ZA
dc.identifier.ris TY - Journal Article AU - Naiker, Suhashni AU - Connolly, Cathy AU - Wiesner, Lubbe AU - Kellerman, Tracey AU - Reddy, Tarylee AU - Harries, Anthony AU - McIlleron, Helen AU - Lienhardt, Christian AU - Pym, Alexander AB - Abstract Background Pharmacokinetic 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 results Sixteen 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. Conclusions A 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 registration ClinicalTrials.gov Identifier: NCT00640887 DA - 2014-11-19 DB - OpenUCT DO - 10.1186/2050-6511-15-61 DP - University of Cape Town J1 - BMC Pharmacology and Toxicology LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy TI - Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy UR - http://hdl.handle.net/11427/13604 ER - en_ZA


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