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Pharmacology

Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis

Elisa H. Ignatius, Mahmoud Tareq Abdelwahab, Bronwyn Hendricks, Nikhil Gupte, Kim Narunsky, Lubbe Wiesner, Grace Barnes, Rodney Dawson, Kelly E. Dooley, Paolo Denti
Elisa H. Ignatius
aJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Mahmoud Tareq Abdelwahab
bUniversity of Cape Town, Division of Clinical Pharmacology, Cape Town, South Africa
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Bronwyn Hendricks
cUniversity of Cape Town Lung Institute, University of Cape Town, Cape Town, South Africa
dDivision of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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Nikhil Gupte
eBJ Government Medical College, Pune, India
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Kim Narunsky
cUniversity of Cape Town Lung Institute, University of Cape Town, Cape Town, South Africa
dDivision of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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Lubbe Wiesner
bUniversity of Cape Town, Division of Clinical Pharmacology, Cape Town, South Africa
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Grace Barnes
aJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Rodney Dawson
cUniversity of Cape Town Lung Institute, University of Cape Town, Cape Town, South Africa
dDivision of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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Kelly E. Dooley
aJohns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Paolo Denti
bUniversity of Cape Town, Division of Clinical Pharmacology, Cape Town, South Africa
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DOI: 10.1128/AAC.01196-20
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ABSTRACT

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 3.35 mg/liter, while median AUC0–24 values were 30.1 and 59.5 mg·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.)

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Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis
Elisa H. Ignatius, Mahmoud Tareq Abdelwahab, Bronwyn Hendricks, Nikhil Gupte, Kim Narunsky, Lubbe Wiesner, Grace Barnes, Rodney Dawson, Kelly E. Dooley, Paolo Denti on behalf of the Assessing Pretomanid for Tuberculosis Study Team
Antimicrobial Agents and Chemotherapy Jan 2021, 65 (2) e01196-20; DOI: 10.1128/AAC.01196-20

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Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis
Elisa H. Ignatius, Mahmoud Tareq Abdelwahab, Bronwyn Hendricks, Nikhil Gupte, Kim Narunsky, Lubbe Wiesner, Grace Barnes, Rodney Dawson, Kelly E. Dooley, Paolo Denti on behalf of the Assessing Pretomanid for Tuberculosis Study Team
Antimicrobial Agents and Chemotherapy Jan 2021, 65 (2) e01196-20; DOI: 10.1128/AAC.01196-20
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KEYWORDS

pretomanid
rifabutin
rifampin
tuberculosis
pharmacokinetic
Mycobacterium tuberculosis
pharmacokinetics

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