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

dc.contributor.authorNaiker, Suhashni
dc.contributor.authorConnolly, Cathy
dc.contributor.authorWiesner, Lubbe
dc.contributor.authorKellerman, Tracey
dc.contributor.authorReddy, Tarylee
dc.contributor.authorHarries, Anthony
dc.contributor.authorMcIlleron, Helen
dc.contributor.authorLienhardt, Christian
dc.contributor.authorPym, Alexander
dc.date.accessioned2015-07-30T03:59:04Z
dc.date.available2015-07-30T03:59:04Z
dc.date.issued2014-11-19
dc.date.updated2015-01-15T17:59:11Z
dc.description.abstractAbstract 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.identifier.apacitationNaiker, 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/11427/13604en_ZA
dc.identifier.chicagocitationNaiker, 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/11427/13604en_ZA
dc.identifier.citationNaiker, 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.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
dc.identifier.urihttp://hdl.handle.net/11427/13604
dc.identifier.urihttp://dx.doi.org/10.1186/2050-6511-15-61
dc.identifier.vancouvercitationNaiker 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.language.rfc3066en
dc.publisher.departmentDivision of Clinical Pharmacologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License*
dc.rights.holderNaiker et al.; licensee BioMed Central Ltd.
dc.rights.urihttp://creativecommons.org/licenses/by/2.0*
dc.sourceBMC Pharmacology and Toxicologyen_ZA
dc.source.urihttp://www.biomedcentral.com/bmcpharmacoltoxicol/
dc.subject.otherRifabutinen_ZA
dc.subject.otherPharmacokineticsen_ZA
dc.subject.otherLopinaviren_ZA
dc.subject.otherTuberculosisen_ZA
dc.subject.otherHIVen_ZA
dc.subject.otherDDIen_ZA
dc.subject.otherRandomizeden_ZA
dc.subject.otherClinical trialen_ZA
dc.subject.otherNeutropeniaen_ZA
dc.subject.otherUveitisen_ZA
dc.titleRandomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy
dc.typeJournal Articleen_ZA
uct.type.filetype
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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