Bactericidal Activity of Pyrazinamide and Clofazimine Alone and in Combinations with Pretomanid and Bedaquiline

Diacon, Andreas H.; Dawson, Rodney; Groote-Bidlingmaier, Florian von; Symons, Greg; Venter, Amour; Donald, Peter R.; Niekerk, Christo van; Everitt, Daniel E.; Hutchings, Jane; Burger, Divan Aristo; Schall, Robert; Mendel, Carl M.

doi:10.1164/rccm.201410-1801oc

Cited by 182 publications

(164 citation statements)

References 25 publications

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“…Therefore, plasma drug concentrations of new drugs such as bedaquiline and delamanid will receive more attention in future studies as well as in daily practice. Also, in cases of off-label use or in studies evaluating the bactericidal activity of drug combinations, information on drug exposure is helpful to explain treatment outcome (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Alffenaar

Bolhuis

Hateren

et al. 2015

Antimicrob Agents Chemother

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dBedaquiline, a diarylquinoline for the treatment of multidrug-resistant tuberculosis (TB), relies on exposure-dependent killing. As data on drug exposure in specific populations are scarce, pharmacokinetic studies may be of interest. No simple and robust validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported to date. Therefore, a new method using a quadrupole mass spectrometer was developed for analysis of bedaquiline and N-monodesmethyl bedaquiline (M2) in human serum, using deuterated bedaquiline as the internal standard. The calibration curve was linear over a range of 0.05 (lower limit of quantification [LLOQ]) to 6.00 mg/liter for both bedaquiline and M2, with correlation coefficient values of 0.997 and 0.999, respectively. The calculated accuracy ranged from 1.9% to 13.6% for bedaquiline and 2.9% to 8.5% for M2. Within-run precision ranged from 3.0% to 7.2% for bedaquiline and 3.1% to 5.2% for M2, and between-run precision ranged from 0.0% to 4.3% for bedaquiline and 0.0% to 4.6% for M2. Evaluation of serum concentrations in a patient receiving bedaquiline showed high levels at the end of treatment, reflecting accumulation of the drug. More observational pharmacokinetic data are needed to relate altered drug concentrations to clinical outcome or adverse drug effects. A simple LC-MS/MS method to quantify bedaquiline and M2 levels in human serum using a deuterated internal standard has been validated. This method can be used in clinical studies and daily practice. Bedaquiline is a diarylquinoline and was approved by the United States Food and Drug Administration (FDA) in 2012 under the accelerated-approval program. This drug is indicated for treatment of multidrug-resistant pulmonary tuberculosis (MDR-TB) in combination with other active anti-TB drugs in adults without other treatment options (1). This new anti-TB drug, formally known as TMC207, showed exposure-dependent killing of Mycobacterium tuberculosis (2, 3). The drug is metabolized by cytochrome P 450 enzyme 3A4 (CYP3A4) to its 5-foldless-active metabolite N-monodesmethyl bedaquiline (M2) (4).Bedaquiline therapy is started in a loading dose of 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks. This dosing regimen was chosen because pharmacokinetics (PK) modeling predicted gradual accumulation in plasma and tissues (4).At this time, little data on PK in patients with advanced MDR-TB or suffering from comorbidities are available apart from the data that were collected in the clinical studies (4). However, variability in the PK of antituberculosis drugs is considerable and altered drug exposure may translate to variations in clinical outcomes (5, 6). Clearly, there is a need for more-descriptive (population) PK studies on bedaquiline to determine predictors of exposure, drug-drug interaction (7), and PK-pharmacodynamics (PD) relationships. The World Health Organization has released a guide for the use of bedaquiline and encourages additional evaluation of this new drug (8).As bedaquilin...

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Section: Discussionmentioning

confidence: 99%

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Alffenaar

Bolhuis

Hateren

et al. 2015

Antimicrob Agents Chemother

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“…353,354 Clofazimine shows no bactericidal activity in patient sputum over the first 14 days of treatment. 355 However, in a phase 2 clinical trial, adding clofazimine at a dose of 100 mg daily for 21 months to multidrug background therapy (ie, the MDR tuberculosis treatment regimen) improved MDR tuberculosis treatment success versus placebo (74% vs 54%). 356 Clofazimine is also considered a key component of a short-course regimen (ie, 9-12 months) recently endorsed by WHO for treatment of MDR tuberculosis after several observational cohorts reported good treatment success.…”

Section: Clofaziminementioning

confidence: 99%

“…Pretomanid is in phase 3 testing, and its characteristics are shown in table 7. On the basis of early bactericidal activity studies 355 and the superior bactericidal activity of pretomanid, moxifloxacin, and pyrazinamide versus rifampicin, isoniazid, pyrazinamide, and ethambutol for drug-sensitive tuberculosis at 8 weeks, 379 the phase 3 STAND study was launched (table 6; NCT02342886), but this study was placed on partial clinical hold because of hepatotoxicity and further enrolment was stopped, but follow up will continue as per protocol. Pretomanid is also being studied as part of combination therapy for XDR tuberculosis (NiX Trial, NCT02333799; table 6).…”

Section: Nitroimidazolesmentioning

confidence: 99%

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

521

474

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“…In a study evaluating a novel regimen, Diacon and colleagues evaluated the 14-day bactericidal activity of clofazimine and pyrazinamide in monotherapy and in combination with pretomanid and bedaquiline (21). Participants with sputum smear-positive pulmonary TB were randomized to receive one of the novel drug combinations or standard therapy.…”

Section: Current and Novel Tb Treatment Regimensmentioning

confidence: 99%

Update in Tuberculosis/Pulmonary Infections 2015

Koenig

Furin

2016

Am J Respir Crit Care Med

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Bactericidal Activity of Pyrazinamide and Clofazimine Alone and in Combinations with Pretomanid and Bedaquiline

Abstract: B-Pa-Z, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new tuberculosis treatment regimen. C had no measurable activity in the first 14 days of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01691534).

Cited by 182 publications

References 25 publications

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Update in Tuberculosis/Pulmonary Infections 2015

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