Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients

Diacon, Andreas H.; Dawson, Rodney; Hanekom, Madeleine; Narunsky, Kim; Venter, Amour; Hittel, Norbert; Geiter, Lawrence; Wells, Charles D.; Paccaly, Anne; Donald, Peter R.

doi:10.5588/ijtld.10.0616

Cited by 186 publications

(149 citation statements)

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“…31 Delamanid (OPC-67683) is a new nitro-hydro-imidazooxazole derivative that inhibits mycolic acid synthesis 32 with encouraging trial results so far. 33,34 It is currently under investigation in phase-III clinical trials as an adjunct to optimised background regimens for treating MDR TB, while other trials are currently evaluating the use of delamanid in children with MDR TB. In 2013, the European Medicine Agency recommended delamanid as a treatment option for TB.…”

Section: New Drugs and Regimensmentioning

confidence: 99%

Clinical implications of the global multidrug-resistant tuberculosis epidemic

Kumar

Abubakar

2016

Clinical Medicine

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Multidrug-resistant tuberculosis (MDR TB) IntroductionThe significant threat of the global multidrug-resistant tuberculosis (MDR TB) epidemic has been described as a crisis in the World Health Organization's (WHO's) End TB strategy .1 MDR TB is defined as tuberculosis (TB) caused by Mycobacterium tuberculosis isolates that are resistant to at least both rifampicin and isoniazid.2 The WHO's Global tuberculosis report supplement in 2014 estimated that MDR TB accounts for 3.5% (95% confidence interval (CI) 2.2-4.7%) of all new cases of TB and 20.5% (95% CI 13.6-27.5%) of TB cases among individuals previously treated for the disease. 3 There were approximately 480,000 new cases of MDR TB globally in 2013, with an estimated 210,000 deaths attributable to MDR TB. The highest levels of MDR TB are in Eastern European and Asian countries, with more than half the global burden of MDR TB being located in India, China and Russia. 4 Additional cause for concern is the emergence of extensively drug-resistant TB (XDR TB), which is defined as tuberculosis caused by M tuberculosis isolates that are resistant to rifampicin, isoniazid, any ABSTRACT fluoroquinolones and at least one of the second-line injectable drugs (capreomycin, kanamycin and amikacin). Here we provide an overview of the importance of MDR TB, its epidemiology, clinical implications, potential ways of addressing the disease and prospects for new diagnostics and treatment. EpidemiologyGlobal epidemiology of TB

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Section: New Drugs and Regimensmentioning

confidence: 99%

Clinical implications of the global multidrug-resistant tuberculosis epidemic

Kumar

Abubakar

2016

Clinical Medicine

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“…Delamanid (OPC-67683), (R)-2-methyl-6-nitro-2-[(4-{4- [4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenoxy) methyl]-2,3-dihydroimidazo [2,1-b]oxazole, is a new antituberculosis agent derived from the nitro-dihydro-im-idazooxazole class of compounds and inhibits mycolic acid synthesis [1]- [3]. Delamanid has been approved as a new drug for the treatment of MDR-TB and launched onto the market in Europe and Japan.…”

Section: Introductionmentioning

confidence: 99%

Liquid Chromatography-Tandem Mass Spectrometry Methods for Determination of Delamanid in Mouse Plasma and Lung

Hirao¹,

Koga²,

Koyama³

et al. 2015

AJAC

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Sensitive and selective liquid chromatography-tandem mass spectrometry methods have been developed and validated for the determination of delamanid in mouse plasma and lung. Sample preparation involved liquid-liquid extraction with diethyl ether for plasma, or protein precipitation followed by liquid-liquid extraction with tert-butyl methyl ether for lung homogenate. Chromatographic separation was performed on a reversed phase column with a linear gradient elution using purified water-formic acid (1000:2, v/v) and methanol-formic acid (1000:2, v/v) at a flow rate of 0.2 mL/min. Detection was performed on a triple-quadrupole tandem mass spectrometer using positive ion electrospray ionization in the selected reaction monitoring mode. The analytical methods were successfully validated for selectivity, calibration curve, accuracy, precision, extraction recovery, and stability over a range of 6 -1000 ng/mL for plasma and 10 -1000 ng/mL for lung homogenate. The validated methods were successfully applied for evaluation of pharmacokinetics of delamanid in male mice.

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“…11) Delamanid inhibits mycolic acid synthesis and has demonstrated potent pre-clinical in vitro and in vivo activity against both drug-susceptible and drug-resistant strains of M. tuberculosis. 12) Further, delamanid has shown anti-TB activity in patients with drug-sensitive TB 13) and in patients with MDR-TB, and is being specifically developed to treat MDR infections. 14,15) Delamanid has been approved as a new drug for the treatment of MDR-TB and has been launched onto the market in Europe and Japan.…”

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confidence: 99%

Delamanid Does Not Inhibit or Induce Cytochrome P450 Enzymes <i>in Vitro</i>

Shimokawa

Sasahara

Yoda

et al. 2014

Biological & Pharmaceutical Bulletin

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Delamanid is a new drug for the treatment of multidrug-resistant tuberculosis. Individuals who are coinfected with human immunodeficiency virus and Mycobacterium tuberculosis may require treatment with a number of medications that might interact significantly with the CYP enzyme system as inhibitors or inducers. It is therefore important to understand how drugs in development for the treatment of tuberculosis will affect CYP enzyme metabolism. The ability of delamanid to inhibit or induce CYP enzymes was investigated in vitro using human liver microsomes or human hepatocytes. Delamanid (100 µM) had little potential for mechanism-based inactivation on eight CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Delamanid's metabolites were noted to inhibit the metabolism of some CYP isoforms, but these effects were observed only at metabolite concentrations that were well above those observed in human plasma during clinical trials. Delamanid (≤10 µM) did not induce CYP1A2, CYP2C9, and CYP3A4 activities in human hepatocytes, and there were no increases in CYP1A2, CYP2B6, CYP2C9, and CYP3A4 mRNA levels. Taken together, these data suggest that delamanid is unlikely to cause clinically relevant drug-drug interactions when co-administered with products that are metabolized by the CYP enzyme system.

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Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients

Abstract: Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity.

Cited by 186 publications

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Clinical implications of the global multidrug-resistant tuberculosis epidemic

Clinical implications of the global multidrug-resistant tuberculosis epidemic

Liquid Chromatography-Tandem Mass Spectrometry Methods for Determination of Delamanid in Mouse Plasma and Lung

Delamanid Does Not Inhibit or Induce Cytochrome P450 Enzymes <i>in Vitro</i>

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