Early Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis

Furin, Jennifer; Bois, Jeannine du; Brakel, Elana van; Chheng, Phalkun; Venter, Amour; Peloquin, Charles A.; Alsultan, Abdullah; Thiel, Bonnie; Debanne, Sara M.; Boom, W. Henry; Diacon, Andreas H.; Johnson, John L.

doi:10.1128/aac.01163-16

Cited by 20 publications

(15 citation statements)

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“…A more recent trial examining the extended sputum EBA using various doses of LCB01–0371 for 15 days (compared to linezolid) is ongoing and currently recruiting patients. Finally, AZD5847 showed modest EBA when dosed at 500 mg and 800 mg twice daily although adverse side effects were apparent at higher doses [45].…”

Section: Drugs and Drug Regimens Under Clinical Developmentmentioning

confidence: 99%

The present state of the tuberculosis drug development pipeline

Libardo

Boshoff

Barry

2018

Current Opinion in Pharmacology

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Tuberculosis now ranks as the leading cause of death in the world due to a single infectious agent. Current standard of care treatment can achieve very high cure rates for drug-sensitive disease but requires a 6-month duration of chemotherapy. Drug-resistant disease requires significantly longer treatment durations with drugs associated with a higher risk of adverse events. Thus, there is a pressing need for a drug regimen that is safer, shorter in duration and superior to current front-line chemotherapy in terms of efficacy. The TB drug pipeline contains several candidates that address one or more of the required attributes of chemotherapeutic regimens that may redefine the standard of care of this disease. Several new drugs have been reported and novel targets have been identified allowing regimens containing new compounds to trickle into clinical studies. Furthermore, a recent paradigm-shift in understanding the pharmacokinetics of anti-tubercular drugs is revolutionizing the way we select compounds for clinical progression.

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Section: Drugs and Drug Regimens Under Clinical Developmentmentioning

confidence: 99%

The present state of the tuberculosis drug development pipeline

Libardo

Boshoff

Barry

2018

Current Opinion in Pharmacology

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“…Patients with suspected miliary or meningeal TB who required immediate combination anti-TB treatment were excluded. Most patients in the study were heavily smear positive, had cavitary disease, and had a high initial sputum bacillary load (4). Patients were randomized to four treatment arms as follows: 500 mg once daily, 500 mg twice daily, 800 mg twice daily, and 1,200 mg once daily.…”

Section: Methodsmentioning

confidence: 99%

“…AZD-5847 is another oxazolidinone derivative under development for the treatment of TB. The drug recently completed a phase IIa clinical trial study to evaluate its pharmacokinetics (PK) and early bactericidal activity at several doses and schedules in patients with drugsusceptible TB (4). The early bactericidal activity of AZD-5847 was very modest in that study.…”

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confidence: 99%

Population Pharmacokinetics of AZD-5847 in Adults with Pulmonary Tuberculosis

Alsultan

Furin

Bois

et al. 2017

Antimicrob Agents Chemother

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AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis (TB). Here we describe the population pharmacokinetics (PK) of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug-susceptible TB. Patients were randomized to four dosages (500 mg once daily, 1,200 mg once daily, 500 mg twice daily, and 800 mg twice daily). Patients were intensively sampled on days 1 and 14. AZD-5847 pharmacokinetics were best described with a two-compartment model with lag time () for absorption. AZD-5847 bioavailability was nonlinear and plateaued at 800 mg. We performed deterministic simulation to compare the PK/pharmacodynamics (PD) of AZD-5847, linezolid, and sutezolid. AZD-5847 PK/PD in terms of both area under the concentration-time curve for the free, unbound fraction (AUC)/MIC and time the free concentration was above the MIC (T>MIC) were less favorable than those for linezolid and sutezolid. This could help explain the poor bactericidal activity of AZD-5847 in the recent phase II study.

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“…Additionally, Furin et al (2016) performed an EBA trial in adults with newly diagnosed sputum smear-positive pulmonary TB. Their findings using AZD-5847 (500 mg twice daily) and HRZE (combination of isoniazid, rifampin, ethambutol, and pyrazinamide) were 0.039 log 10 and 0.163 log 10 CFU/mL/day, respectively, by day 14 [ 138 ]. This is a significant decline in the number of CFU over time in favor of AZD-5847 at twice-daily doses of 500 mg, whereas there is no bacterial activity detected at 500 mg once daily doses of AZD-5847 [ 141 ].…”

Section: Novel Anti-mtb Agentsmentioning

confidence: 99%

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

2021

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern; herein, we have compiled drug-drug interaction reports, as well as efficacy reports for drug combinations studies involving antitubercular agents in clinical development.

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Early Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis

Cited by 20 publications

References 15 publications

The present state of the tuberculosis drug development pipeline

The present state of the tuberculosis drug development pipeline

Population Pharmacokinetics of AZD-5847 in Adults with Pulmonary Tuberculosis

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

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