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Scott G Franzblau - One of the best experts on this subject based on the ideXlab platform.

  • 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis
    Journal of medicinal chemistry, 2017
    Co-Authors: Andrew M. Thompson, Andrew J. Marshall, Vanessa Yardley, Louis Maes, Suman Gupta, Delphine Launay, Stephanie Braillard, Eric Chatelain, Patrick D. O'connor, Scott G Franzblau
    Abstract:

    Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from Delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of Delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.

  • 7‑Substituted 2‑Nitro-5,6-dihydroimidazo[2,1‑b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis
    2017
    Co-Authors: Andrew M. Thompson, Patrick D. O’connor, Andrew J. Marshall, Vanessa Yardley, Louis Maes, Suman Gupta, Delphine Launay, Stephanie Braillard, Eric Chatelain, Scott G Franzblau
    Abstract:

    Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from Delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of Delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo­[2,1-b]­[1,3]­oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate

  • in vitro and in vivo activities of the nitroimidazole tba 354 against mycobacterium tuberculosis
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Anna M Upton, Khisimuzi Mdluli, T. J. Yang, Yuehong Wang, B Wang, Yu Lu, Jian Xu, Scott G Franzblau
    Abstract:

    Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole Delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of Delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10−7. In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of Delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.

Lawrence Geiter - One of the best experts on this subject based on the ideXlab platform.

  • Delamanid from discovery to its use for pulmonary multidrug resistant tuberculosis mdr tb
    Tuberculosis, 2018
    Co-Authors: Yongge Liu, Lawrence Geiter, Makoto Matsumoto, Rajesh Gupta, Hidekaza Ishida, Kinue Ohguro, Masuhiro Yoshitake, Jeffrey Hafkin
    Abstract:

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is the leading cause of death from an infectious disease globally. The widespread and ever-increasing resistance to TB drugs is reducing the effectiveness of treatment and jeopardizing TB control. New effective drugs with acceptable safety profiles are needed to turn the tide. Since the early 1990s, Otsuka Pharmaceutical Co., Ltd. has had a TB drug development program that resulted in the selection and development of Delamanid (OPC-67683, Deltyba®), a first-in-class bicyclic nitroimidazole. Delamanid was initially approved by the European Medicines Agency (EMA) in 2014 for the treatment of adult pulmonary multi-drug resistant (MDR)-TB when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. It has since been approved by several other countries/regions. In this review, we describe the history of Delamanid's development, including the screening process, in vitro and in vivo characterization, as well as various clinical studies. Delamanid possesses potent activity against replicating, dormant, and intracellular MTB bacilli, and is bactericidal in mouse and guinea pig TB models. Delamanid resistance mechanisms have been attributed to genes in the F420-dependent deazaflavin nitroreductase bio-activation pathway, found in mycobacterium species but not in common bacterial or mammalian cells. Published susceptibility testing results from 744 clinical isolates from Delamanid-naive patients indicate that the natural resistance rate to Delamanid is very low (1.3%). Delamanid is largely metabolized by albumin in serum, and to a much less extent by cytochrome P450 enzymes. Furthermore, it neither inhibits nor induces P450 enzymes. In terms of efficacy, Delamanid demonstrated activity in an early bactericidal activity trial in drug susceptible pulmonary TB patients and increased 2-month sputum culture conversion rates when added to an optimized background regimen in MDR-TB patients in a phase 2b global clinical trial. In addition, recent results outside clinical studies show favourable responses in highly resistant TB patients including extensively drug resistant (XDR)-TB when treated with Delamanid-containing regimens in routine programmatic settings. The primary safety concern with Delamanid is QTcF interval prolongation, although this observation has thus far not been associated with any clinical cardiac events. Overall, Delamanid appears to be a well-tolerated and safe anti-TB drug when compared to other drugs used to treat MDR-TB.

  • Delamanid coadministered with antiretroviral drugs or antituberculosis drugs shows no clinically relevant drug drug interactions in healthy subjects
    Antimicrobial Agents and Chemotherapy, 2016
    Co-Authors: Suresh Mallikaarjun, Charles D. Wells, Carolyn Petersen, Anne Paccaly, Susan E Shoaf, Shiva Patil, Lawrence Geiter
    Abstract:

    Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between Delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for Delamanid, Delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of Delamanid with tenofovir or efavirenz did not affect the PK characteristics of Delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with Delamanid resulted in an approximately 25% higher Delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by Delamanid. Coadministration of Delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower Delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with Delamanid coadministration. The lack of clinically significant drug-drug interactions between Delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the Delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to decreased Delamanid absorption and not to CYP induction.

  • mic of Delamanid opc 67683 against mycobacterium tuberculosis clinical isolates and a proposed critical concentration
    Antimicrobial Agents and Chemotherapy, 2016
    Co-Authors: Kelly Stinson, Natalia Kurepina, Amour Venter, Mamoru Fujiwara, Elena Shashkina, Juliano Timm, Masanori Kawasaki, Barry N Kreiswirth, Makoto Matsumoto, Lawrence Geiter
    Abstract:

    The increasing global burden of multidrug-resistant tuberculosis (MDR-TB) requires reliable drug susceptibility testing that accurately characterizes susceptibility and resistance of pathogenic bacteria to effectively treat patients with this deadly disease. Delamanid is an anti-TB agent first approved in the European Union in 2014 for the treatment of pulmonary MDR-TB in adults. Using the agar proportion method, Delamanid MIC was determined for 460 isolates: 316 from patients enrolled in a phase 2 global clinical trial, 76 from two phase 2 early bactericidal activity trials conducted in South Africa, and 68 isolates obtained outside clinical trials (45 from Japanese patients and 23 from South African patients). With the exception of two isolates, MICs ranged from 0.001 to 0.05 μg/ml, resulting in an MIC50 of 0.004 μg/ml and an MIC90 of 0.012 μg/ml. Various degrees of resistance to other anti-TB drugs did not affect the distribution of MICs, nor did origin of isolates from regions/countries other than South Africa. A critical concentration/breakpoint of 0.2 μg/ml can be used to define susceptible and resistant isolates based on the distribution of MICs and available pharmacokinetic data. Thus, clinical isolates from Delamanid-naive patients with tuberculosis have a very low MIC for Delamanid and baseline resistance is rare, demonstrating the potential potency of Delamanid and supporting its use in an optimized background treatment regimen for MDR-TB.

  • Delamanid for Extensively Drug-Resistant Tuberculosis
    The New England journal of medicine, 2015
    Co-Authors: Rajesh Gupta, Lawrence Geiter, Charles D. Wells, Mengqui Gao, Andra Cirule, Heping Xiao
    Abstract:

    Therapeutic options for extensively drug-resistant tuberculosis infection are limited. In this post-hoc analysis, a new drug, Delamanid, shows some activity in the treatment of XDR-TB.

  • long term mortality assessment of multidrug resistant tuberculosis patients treated with Delamanid
    European Respiratory Journal, 2015
    Co-Authors: Charles D. Wells, Rajesh Gupta, Norbert Hittel, Lawrence Geiter
    Abstract:

    MDR-TB patients treated with 6 months or more of Delamanid had significantly lower likelihood of mortality http://ow.ly/HOv1d

Rajesh Gupta - One of the best experts on this subject based on the ideXlab platform.

  • Delamanid from discovery to its use for pulmonary multidrug resistant tuberculosis mdr tb
    Tuberculosis, 2018
    Co-Authors: Yongge Liu, Lawrence Geiter, Makoto Matsumoto, Rajesh Gupta, Hidekaza Ishida, Kinue Ohguro, Masuhiro Yoshitake, Jeffrey Hafkin
    Abstract:

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is the leading cause of death from an infectious disease globally. The widespread and ever-increasing resistance to TB drugs is reducing the effectiveness of treatment and jeopardizing TB control. New effective drugs with acceptable safety profiles are needed to turn the tide. Since the early 1990s, Otsuka Pharmaceutical Co., Ltd. has had a TB drug development program that resulted in the selection and development of Delamanid (OPC-67683, Deltyba®), a first-in-class bicyclic nitroimidazole. Delamanid was initially approved by the European Medicines Agency (EMA) in 2014 for the treatment of adult pulmonary multi-drug resistant (MDR)-TB when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. It has since been approved by several other countries/regions. In this review, we describe the history of Delamanid's development, including the screening process, in vitro and in vivo characterization, as well as various clinical studies. Delamanid possesses potent activity against replicating, dormant, and intracellular MTB bacilli, and is bactericidal in mouse and guinea pig TB models. Delamanid resistance mechanisms have been attributed to genes in the F420-dependent deazaflavin nitroreductase bio-activation pathway, found in mycobacterium species but not in common bacterial or mammalian cells. Published susceptibility testing results from 744 clinical isolates from Delamanid-naive patients indicate that the natural resistance rate to Delamanid is very low (1.3%). Delamanid is largely metabolized by albumin in serum, and to a much less extent by cytochrome P450 enzymes. Furthermore, it neither inhibits nor induces P450 enzymes. In terms of efficacy, Delamanid demonstrated activity in an early bactericidal activity trial in drug susceptible pulmonary TB patients and increased 2-month sputum culture conversion rates when added to an optimized background regimen in MDR-TB patients in a phase 2b global clinical trial. In addition, recent results outside clinical studies show favourable responses in highly resistant TB patients including extensively drug resistant (XDR)-TB when treated with Delamanid-containing regimens in routine programmatic settings. The primary safety concern with Delamanid is QTcF interval prolongation, although this observation has thus far not been associated with any clinical cardiac events. Overall, Delamanid appears to be a well-tolerated and safe anti-TB drug when compared to other drugs used to treat MDR-TB.

  • final treatment outcomes of multidrug and extensively drug resistant tuberculosis patients in latvia receiving Delamanid containing regimens
    European Respiratory Journal, 2017
    Co-Authors: Liga Kuksa, Linda Barkane, Norbert Hittel, Rajesh Gupta
    Abstract:

    Final treatment outcomes from the first cohort of Delamanid MDR-TB patients in Latvia support its safety and efficacy http://ow.ly/6Mhy30fPv2f

  • early outcomes in mdr tb and xdr tb patients treated with Delamanid under compassionate use
    European Respiratory Journal, 2017
    Co-Authors: Jeffrey Hafkin, Alexandra Martin, Norbert Hittel, Rajesh Gupta
    Abstract:

    Early data from the CU programme show Delamanid may be effective in MDR/XDR-TB with few treatment options http://ow.ly/tA6Y30cs2Yg

  • Delamanid for Extensively Drug-Resistant Tuberculosis
    The New England journal of medicine, 2015
    Co-Authors: Rajesh Gupta, Lawrence Geiter, Charles D. Wells, Mengqui Gao, Andra Cirule, Heping Xiao
    Abstract:

    Therapeutic options for extensively drug-resistant tuberculosis infection are limited. In this post-hoc analysis, a new drug, Delamanid, shows some activity in the treatment of XDR-TB.

  • long term mortality assessment of multidrug resistant tuberculosis patients treated with Delamanid
    European Respiratory Journal, 2015
    Co-Authors: Charles D. Wells, Rajesh Gupta, Norbert Hittel, Lawrence Geiter
    Abstract:

    MDR-TB patients treated with 6 months or more of Delamanid had significantly lower likelihood of mortality http://ow.ly/HOv1d

Norbert Hittel - One of the best experts on this subject based on the ideXlab platform.

Jeffrey Hafkin - One of the best experts on this subject based on the ideXlab platform.

  • population pharmacokinetic and concentration qtc analysis of Delamanid in pediatric participants with multidrug resistant tuberculosis
    Antimicrobial Agents and Chemotherapy, 2021
    Co-Authors: Tomohiro Sasaki, Elin M Svensson, Xiaofeng Wang, Yanlin Wang, Jeffrey Hafkin, Mats O Karlsson, Suresh Mallikaarjun
    Abstract:

    A population pharmacokinetic analysis of Delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of Delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 to 17 years old, enrolled in 2 clinical trials, were utilized for the analysis. The final dataset contained 634 Delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of Delamanid. Two compartment models for each component with linear elimination were selected to characterize the disposition of Delamanid and DM-6705, respectively. The covariates included in the model were body weight on apparent volume of distribution and apparent clearance (for both Delamanid and DM-6705); formulation (dispersible vs film coated tablet) on mean absorption time; age, formulation, and dose on bioavailability of Delamanid; age on the fraction of Delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in Delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB, QT corrected by Bazett's' formula) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc value were less than 10 ms at the simulated Cmax of DM-6705 following administration of maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive Delamanid.

  • compassionate use of Delamanid in adults and children for drug resistant tuberculosis 5 year update
    European Respiratory Journal, 2021
    Co-Authors: Sambuddha Ghosh, Jeffrey Hafkin, Lusine Breitscheidel, Natasa Lazarevic, Alexandra Martin, Norbert Hittel
    Abstract:

    Background Although Delamanid has been approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in numerous regions, in areas where it is not yet registered, it can be accessed as part of salvage therapy—in particular, for those patients with limited treatment options—via the Otsuka Compassionate Use (CU) programme. Here we present the analysis of interim treatment outcomes by 24 weeks of more than 200 multidrug-resistant tuberculosis (MDR-TB) patients globally who received Delamanid under the Otsuka CU programme. Methods We evaluated the treatment efficacy, with respect to culture negativity at 24 weeks, and safety profile of Delamanid in a MDR-TB cohort of patients treated under CU between 2014 and 2019. Results Among patients who received Delamanid as part of a multidrug regimen, 123/202 (61%) had extensively drug-resistant tuberculosis (XDR-TB), 66/202 (33%) had HIV co-infection, and 34/202 (17%) were children ages between 6 and 17 years. Of those patients who were culture positive at Delamanid treatment initiation and completed 24 weeks of Delamanid treatment in combination with other anti-TB drugs, culture negativity was achieved in 116/147 (79%). The corresponding rates of culture negativity for patients with XDR-TB, HIV co-infection, and the paediatric subgroup were 69/90 (77%), 44/48 (92%), and 20/25 (80%), respectively. QT interval prolongation was the most frequently observed serious adverse event (reported in 8% of patients receiving Delamanid). Overall, treatment safety outcomes did not reveal any new or unidentified risks. Conclusions The use of Delamanid combined with other active drugs has the potential to achieve high rates of culture negativity in difficult-to-treat drug-resistant tuberculosis cases, with a favourable safety profile.

  • Delamanid from discovery to its use for pulmonary multidrug resistant tuberculosis mdr tb
    Tuberculosis, 2018
    Co-Authors: Yongge Liu, Lawrence Geiter, Makoto Matsumoto, Rajesh Gupta, Hidekaza Ishida, Kinue Ohguro, Masuhiro Yoshitake, Jeffrey Hafkin
    Abstract:

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is the leading cause of death from an infectious disease globally. The widespread and ever-increasing resistance to TB drugs is reducing the effectiveness of treatment and jeopardizing TB control. New effective drugs with acceptable safety profiles are needed to turn the tide. Since the early 1990s, Otsuka Pharmaceutical Co., Ltd. has had a TB drug development program that resulted in the selection and development of Delamanid (OPC-67683, Deltyba®), a first-in-class bicyclic nitroimidazole. Delamanid was initially approved by the European Medicines Agency (EMA) in 2014 for the treatment of adult pulmonary multi-drug resistant (MDR)-TB when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. It has since been approved by several other countries/regions. In this review, we describe the history of Delamanid's development, including the screening process, in vitro and in vivo characterization, as well as various clinical studies. Delamanid possesses potent activity against replicating, dormant, and intracellular MTB bacilli, and is bactericidal in mouse and guinea pig TB models. Delamanid resistance mechanisms have been attributed to genes in the F420-dependent deazaflavin nitroreductase bio-activation pathway, found in mycobacterium species but not in common bacterial or mammalian cells. Published susceptibility testing results from 744 clinical isolates from Delamanid-naive patients indicate that the natural resistance rate to Delamanid is very low (1.3%). Delamanid is largely metabolized by albumin in serum, and to a much less extent by cytochrome P450 enzymes. Furthermore, it neither inhibits nor induces P450 enzymes. In terms of efficacy, Delamanid demonstrated activity in an early bactericidal activity trial in drug susceptible pulmonary TB patients and increased 2-month sputum culture conversion rates when added to an optimized background regimen in MDR-TB patients in a phase 2b global clinical trial. In addition, recent results outside clinical studies show favourable responses in highly resistant TB patients including extensively drug resistant (XDR)-TB when treated with Delamanid-containing regimens in routine programmatic settings. The primary safety concern with Delamanid is QTcF interval prolongation, although this observation has thus far not been associated with any clinical cardiac events. Overall, Delamanid appears to be a well-tolerated and safe anti-TB drug when compared to other drugs used to treat MDR-TB.

  • early outcomes in mdr tb and xdr tb patients treated with Delamanid under compassionate use
    European Respiratory Journal, 2017
    Co-Authors: Jeffrey Hafkin, Alexandra Martin, Norbert Hittel, Rajesh Gupta
    Abstract:

    Early data from the CU programme show Delamanid may be effective in MDR/XDR-TB with few treatment options http://ow.ly/tA6Y30cs2Yg