TY - JOUR
T1 - Pretomanid pharmacokinetics in the presence of rifamycins
T2 - Interim results from a randomized trial among patients with tuberculosis
AU - Assessing Pretomanid for Tuberculosis Study Team
AU - Ignatius, Elisa H.
AU - Abdelwahab, Mahmoud Tareq
AU - Hendricks, Bronwyn
AU - Gupte, Nikhil
AU - Narunsky, Kim
AU - Wiesner, Lubbe
AU - Barnes, Grace
AU - Dawson, Rodney
AU - Dooley, Kelly E.
AU - Denti, Paolo
AU - Carstens, Debbie
AU - Smits, Tanya
AU - Whitlaw, Coleen
AU - Truter, Ide
N1 - Funding Information:
This trial was funded by the FDA’s Orphan Products Grants Program (FD-R-004794-01). E.H.I. was supported by T32 GM066691-17. K.E.D. is supported by K24AI150349. The National Research Foundation provided funding to P.D. (grant 109056). M.T.A. and P.D. were supported by the Swedish Foundation for International Cooperation in Research and Higher Education (STINT) jointly with the South African National Research Council, National Research Foundation (NRF) (NRF grant 101575). Pretomanid was donated by the Global Alliance for Tuberculosis Research (TB Alliance). Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. UM1 AI068634, UM1 AI068636, and UM1 AI106701.
Funding Information:
We also acknowledge the support of the Division of Clinical Pharmacology, analytical laboratory, and ICTS High Performance Computing team: http://hpc.uct.ac.za. at University of Cape Town. We acknowledge the AIDS Clinical Trials Group (ACTG) for its support of this analysis and provision of data from A5306. This trial was funded by the FDA's Orphan Products Grants Program (FD-R-004794-01). E.H.I. was supported by T32 GM066691-17. K.E.D. is supported by K24AI150349. The National Research Foundation provided funding to P.D. (grant 109056). M.T.A. and P.D. were supported by the Swedish Foundation for International Cooperation in Research and Higher Education (STINT) jointly with the South African National Research Council, National Research Foundation (NRF) (NRF grant 101575). Pretomanid was donated by the Global Alliance for Tuberculosis Research (TB Alliance). Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. UM1 AI068634, UM1 AI068636, and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
Copyright © 2021 American Society for Microbiology. All Rights Reserved.
PY - 2021/2
Y1 - 2021/2
N2 - Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid. Pretomanid may also have benefit as a treatment-shortening agent for drug-sensitive tuberculosis. It is unclear how and whether it can be used together with rifamycins, which are key sterilizing first-line drugs. In this analysis, data were pooled from two studies: the Assessing Pretomanid for Tuberculosis (APT) trial, in which patients with drug-sensitive pulmonary TB received pretomanid, isoniazid, and pyrazinamide plus either rifampin or rifabutin versus standard of care under fed conditions, and the AIDS Clinical Trials Group 5306 (A5306) trial, a phase I study in healthy volunteers receiving pretomanid alone or in combination with rifampin under fasting conditions. In our population pharmacokinetic (PK) model, participants taking rifampin had 44.4 and 59.3% reductions in pretomanid AUC (area under the concentration-time curve) compared to those taking rifabutin or pretomanid alone (due to 80 or 146% faster clearance) in the APT and A5306 trials, respectively. Median maximum concentrations (Cmax) in the rifampin and rifabutin arms were 2.14 and 3.35mg/liter, while median AUC0-24 values were 30.1 and 59.5mg·h/liter, respectively. Though pretomanid exposure in APT was significantly reduced with rifampin, AUC0-24 values were similar to those associated with effective treatment in registrational trials, likely because APT participants were fed with dosing, enhancing pretomanid relative bioavailability and exposures. Pretomanid concentrations with rifabutin were high but in range with prior observations. While pretomanid exposures with rifampin are unlikely to impair efficacy, our data suggest that pretomanid should be taken with food if prescribed with rifampin. (This study has been registered at ClinicalTrials.gov under identifier NCT02256696).
AB - Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid. Pretomanid may also have benefit as a treatment-shortening agent for drug-sensitive tuberculosis. It is unclear how and whether it can be used together with rifamycins, which are key sterilizing first-line drugs. In this analysis, data were pooled from two studies: the Assessing Pretomanid for Tuberculosis (APT) trial, in which patients with drug-sensitive pulmonary TB received pretomanid, isoniazid, and pyrazinamide plus either rifampin or rifabutin versus standard of care under fed conditions, and the AIDS Clinical Trials Group 5306 (A5306) trial, a phase I study in healthy volunteers receiving pretomanid alone or in combination with rifampin under fasting conditions. In our population pharmacokinetic (PK) model, participants taking rifampin had 44.4 and 59.3% reductions in pretomanid AUC (area under the concentration-time curve) compared to those taking rifabutin or pretomanid alone (due to 80 or 146% faster clearance) in the APT and A5306 trials, respectively. Median maximum concentrations (Cmax) in the rifampin and rifabutin arms were 2.14 and 3.35mg/liter, while median AUC0-24 values were 30.1 and 59.5mg·h/liter, respectively. Though pretomanid exposure in APT was significantly reduced with rifampin, AUC0-24 values were similar to those associated with effective treatment in registrational trials, likely because APT participants were fed with dosing, enhancing pretomanid relative bioavailability and exposures. Pretomanid concentrations with rifabutin were high but in range with prior observations. While pretomanid exposures with rifampin are unlikely to impair efficacy, our data suggest that pretomanid should be taken with food if prescribed with rifampin. (This study has been registered at ClinicalTrials.gov under identifier NCT02256696).
KW - Mycobacterium tuberculosis
KW - Pharmacokinetic
KW - Pharmacokinetics
KW - Pretomanid
KW - Rifabutin
KW - Rifampin
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85099974621&partnerID=8YFLogxK
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U2 - 10.1128/AAC.01196-20
DO - 10.1128/AAC.01196-20
M3 - Article
C2 - 33229425
AN - SCOPUS:85099974621
VL - 65
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 2
M1 - e01196-20
ER -