Chemistry:Omadacycline

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Short description: Chemical compound
Omadacycline
Omadacycline.svg
Clinical data
Pronunciationoh mad" a sye' kleen
Trade namesNuzyra
Other namesPTK-0796,[1] BAY 73-6944
AHFS/Drugs.comMonograph
MedlinePlusa618066
License data
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC29H40N4O7
Molar mass556.660 g·mol−1
3D model (JSmol)

Omadacycline, sold under the brand name Nuzyra, is a broad spectrum antibiotic medication belonging to the aminomethylcycline subclass[3] of tetracycline antibiotics. In the United States, it was approved in October 2018, for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections.[2][4]

Mechanism of action

The mechanism of action of omadacycline is similar to that of other tetracyclines – inhibition of bacterial protein synthesis. Omadacycline has activity against bacterial strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection).[5]

History

Omadacycline was invented at Tufts University School of Medicine by a research team led by Mark L. Nelson with Mohamed Ismail while at Tufts and Kwasi Ohemeng and Laura Honeyman at Paratek Pharmaceuticals, Boston. The team applying their chemistry methods to the tetracycline scaffolds created over 3000 new derivatives, leading to the novel third-generation compounds omadacycline and sarecycline.[6]

In vitro studies

In vitro studies have shown that omadacycline has activity against a broad range of Gram-positive and select Gram-negative pathogens.[7] Omadacycline has potent in vitro activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant and multi-drug resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus. Omadacycline also has antimicrobial activity against common Gram-negative aerobes, some anaerobes, and atypical bacteria such as Legionella and Chlamydia.[8] This activity translated to potent efficacy for omadacycline in an in vivo systemic infection model in mice.[9]

Additional in vitro and in vivo studies of omadacycline metabolism, disposition, and drug interactions show that omadacycline is metabolically stable (i.e., it does not undergo significant biotransformation) and neither inhibits nor interacts with metabolizing enzymes or transporters.[10]

Clinical trials

A phase II study was conducted comparing the safety and efficacy of omadacycline to linezolid for the treatment of complicated skin and skin structure infections. Patients were randomized at 11 sites in the US to receive either omadacycline 100 mg intravenously once daily with an option to transition to 200 mg orally once daily or linezolid 600 mg intravenously twice daily with an option to transition to 600 mg orally twice daily. The results indicated that omadacycline is well tolerated and has the potential to be an effective treatment in patients with complicated skin and skin structure infections.[11]

In June 2013, the US Food and Drug Administration (FDA) designated the intravenous and oral formulations of omadacycline as a qualified infectious disease product in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.[12]

A 650-patient phase III registration study comparing omadacycline to linezolid for the treatment of acute bacterial skin and skin structure infections began in June 2015.[13][14] Omadacycline met the primary efficacy endpoint of early clinical response with statistical non-inferiority (10% margin) compared to linezolid, and was generally safe and well tolerated. The most common treatment-emergent adverse events were gastrointestinal side effects (18.0% for omadacycline vs. 15.8% for linezolid).[15]

A 750-patient phase III study comparing omadacycline to moxifloxacin for the treatment of community-acquired bacterial pneumonia began in November 2015.[16] Omadacycline was statistically non-inferior to moxifloxacin at the early clinical response, 72 to 120 hours after therapy was initiated.[17]

In May 2016, a phase Ib study of omadacycline in urinary tract infection was initiated.[18]

In August 2016, a second phase III study of omadacycline was initiated in patients with acute bacterial skin and skin structure infections, comparing the efficacy and safety of once-daily, oral omadacycline to that of twice-daily, oral linezolid.[19] In July 2017, analysis of the data showed that all of the primary and secondary endpoints required for submission to the FDA and EMA were met. This was the third phase 3 registration study of omadacycline with favorable results.[20]

References

  1. ↑ Boggs, Jennifer. "Antibiotic Firm Paratek Joins IPO Queue; Aiming for $92M". Clarivate Analytics. http://www.bioworld.com/content/antibiotic-firm-paratek-joins-ipo-queue-aiming-92m-0. 
  2. ↑ 2.0 2.1 "Nuzyra- omadacycline injection, powder, lyophilized, for solution; Nuzyra- omadacycline tablet, film coated". 3 June 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51591524-4703-44c6-8bde-dce3e6a463d1. 
  3. ↑ "Structure-activity relationship of the aminomethylcyclines and the discovery of omadacycline". Antimicrobial Agents and Chemotherapy 59 (11): 7044–53. November 2015. doi:10.1128/AAC.01536-15. PMID 26349824. 
  4. ↑ "Drug Approval Package: Nuzyra". 8 November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209816Orig1s000,209817Orig1s000TOC.cfm. 
  5. ↑ "Mechanism of action of the novel aminomethylcycline antibiotic omadacycline". Antimicrobial Agents and Chemotherapy 58 (3): 1279–83. March 2014. doi:10.1128/AAC.01066-13. PMID 24041885. 
  6. ↑ Nelson ML, Ohemeng K, "4-dedimethylamino tetracycline compounds", US patent 7056902, published 6 June 2006, assigned to Paratek Pharmaceuticals Inc.
  7. ↑ "In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline". Antimicrobial Agents and Chemotherapy 60 (9): 5247–53. September 2016. doi:10.1128/AAC.00320-16. PMID 27324778. 
  8. ↑ "Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections". Future Microbiology 11 (11): 1421–1434. October 2016. doi:10.2217/fmb-2016-0100. PMID 27539442. 
  9. ↑ "In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline". Antimicrobial Agents and Chemotherapy 58 (2): 1127–35. February 2014. doi:10.1128/AAC.01242-13. PMID 24295985. 
  10. ↑ "Clinical disposition, metabolism and in vitro drug-drug interaction properties of omadacycline". Xenobiotica; the Fate of Foreign Compounds in Biological Systems 47 (8): 682–696. August 2017. doi:10.1080/00498254.2016.1213465. PMID 27499331. 
  11. ↑ "A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of linezolid for treatment of complicated skin and skin structure infections". Antimicrobial Agents and Chemotherapy 56 (11): 5650–4. November 2012. doi:10.1128/AAC.00948-12. PMID 22908151. 
  12. ↑ "Paratek Pharmaceuticals Announces FDA Grant of Qualified Infectious Disease Product (QIDP) Designation for Its Lead Product Candidate, Omadacycline" (Press release). Paratek Pharmaceuticals. 3 January 2013. Retrieved 17 October 2017 – via PR Newswire.
  13. ↑ Seiffert, Don (2015). "Paratek presents new trial data for antibiotic as late-stage trials continue". American City Business Journals. http://www.bizjournals.com/boston/blog/bioflash/2016/04/paratek-presents-new-trial-data-for-antibiotic-as.html. 
  14. ↑ Clinical trial number NCT02378480 for "Omadacycline Versus Linezolid for the Treatment of ABSSSI (EudraCT #2013-003644-23)" at ClinicalTrials.gov
  15. ↑ "Paratek Announces that Omadacycline Met All Primary and Secondary Efficacy Outcomes Designated by FDA and EMA in a Phase 3 Study in Acute Bacterial Skin Infections; Omadacycline was Generally Safe and Well-Tolerated" (Press release). Paratek Pharmaceuticals. 16 June 2016. Retrieved 3 July 2016 – via GlobeNewswire.
  16. ↑ Clinical trial number NCT02531438 for "Omadacycline vs Moxifloxacin for the Treatment of CABP (EudraCT #2013-004071-13)" at ClinicalTrials.gov
  17. ↑ "Paratek Announces Positive Phase 3 Study of Omadacycline in Community-Acquired Bacterial Pneumonia" (Press release). Paratek Pharmaceuticals. 3 April 2017. Retrieved 16 May 2017 – via GlobeNewswire.
  18. ↑ "Paratek Initiates Phase 1b Study of Omadacycline in Urinary Tract Infection" (Press release). Paratek Pharmaceuticals. 2 May 2016. Retrieved 3 July 2016 – via GlobeNewswire.
  19. ↑ "Paratek Initiates Phase 3 Study of Oral-only Omadacycline in ABSSSI" (Press release). Paratek Pharmaceuticals. 15 August 2016. Retrieved 15 August 2016 – via GlobeNewswire.
  20. ↑ "Paratek Announces Phase 3 Study of Oral-Only Dosing of Omadacycline Met All Primary and Secondary FDA and EMA Efficacy Endpoints in Acute Bacterial Skin Infections" (Press release). Paratek Pharmaceuticals. 17 July 2017. Retrieved 19 July 2017 – via GlobeNewswire.

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