Omadacycline tosylate (formerly PTK0796; trade name: Nuzyra), the tosylate salt of omadacycline, is a tetracycline antibiotic being developed as an oral and intravenous (IV) formulation to treat community-acquired bacterial infections such as acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). In Oct 2018, Omadacycline was approved by FDA to treat community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections.
Physicochemical Properties
| Molecular Formula | C36H48N4O10S |
| Molecular Weight | 728.86 |
| Exact Mass | 728.309 |
| Elemental Analysis | C, 59.33; H, 6.64; N, 7.69; O, 21.95; S, 4.40 |
| CAS # | 1075240-43-5 |
| Related CAS # | Omadacycline;389139-89-3;Omadacycline hydrochloride;1196800-39-1;Omadacycline-d9;2272886-41-4;Omadacycline mesylate;1196800-40-4 |
| PubChem CID | 54746485 |
| Appearance | White to yellow solid powder |
| LogP | 4.736 |
| Hydrogen Bond Donor Count | 7 |
| Hydrogen Bond Acceptor Count | 13 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 51 |
| Complexity | 1350 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | S(C1C([H])=C([H])C(C([H])([H])[H])=C([H])C=1[H])(=O)(=O)O[H].O([H])[C@@]12C(=C(C(N([H])[H])=O)C([C@]([H])([C@]1([H])C([H])([H])[C@]1([H])C([H])([H])C3=C(C([H])=C(C([H])([H])N([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C(=C3C(=C1C2=O)O[H])O[H])N(C([H])([H])[H])C([H])([H])[H])N(C([H])([H])[H])C([H])([H])[H])=O)O[H] |
| InChi Key | SETFNHZTVGTBHC-XGLFQKEBSA-N |
| InChi Code | InChI=1S/C29H40N4O7.C7H8O3S/c1-28(2,3)12-31-11-14-10-17(32(4)5)15-8-13-9-16-21(33(6)7)24(36)20(27(30)39)26(38)29(16,40)25(37)18(13)23(35)19(15)22(14)34;1-6-2-4-7(5-3-6)11(8,9)10/h10,13,16,21,31,34,36-37,40H,8-9,11-12H2,1-7H3,(H2,30,39);2-5H,1H3,(H,8,9,10)/t13-,16-,21-,29-;/m0./s1 |
| Chemical Name | (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-((neopentylamino)methyl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide 4-methylbenzenesulfonate |
| Synonyms | PTK 0796 tosylate; PTK-0796; PTK0796; Omadacycline (tosylate); Omadacycline tosylate [USAN]; Omadacycline tosilate; Amadacyclintosylate |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Tetracycline; protein synthesis of bacteria | ||
| ln Vitro | Omadacycline is a novel, aminomethyl tetracycline antibiotic being developed for oral and intravenous (IV) administration to treat community-acquired bacterial infections such as acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). In vitro, omadacycline has activity against Gram-positive and Gram-negative aerobes, anaerobes, and atypical pathogens including Legionella and Chlamydia spp. Omadacycline offers once daily oral and IV dosing and a clinical tolerability and safety profile that compares favorably with contemporary antibiotics used across serious community-acquired infections where resistance has rendered many less effective. In studies in patients with complicated skin and skin structure infections, including those with MRSA infections, omadacycline exhibited an efficacy and tolerability profile that was comparable to linezolid. Ongoing and planned clinical studies are evaluating omadacycline as monotherapy for treating serious community-acquired bacterial infections including Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and Community-Acquired Bacterial Pneumonia (CABP). This review provides an overview of the discovery, microbiology, nonclinical data, and available clinical safety and efficacy data for omadacycline, with reference to other contemporary tetracycline-derived antibiotics. | ||
| ln Vivo |
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| Enzyme Assay |
In vitro stability and drug–drug interaction potential of omadacycline[6] The stability of omadacycline (4.8 and 48 μM) was assessed in human microsomes and hepatocytes. After 30 min incubation of omadacycline in human microsomes, >90% of omadacycline was recovered intact. Similarly, after incubation of omadacycline up to 24 h in human hepatocytes, >86% was recovered intact. These results indicate that omadacycline is not metabolized to any significant extent.The potential for drug-drug-interactions with omadacycline was assessed using either pooled human liver microsome preparations, S9, liver cytosol, or recombinant flavin monooxygenases (FMO1, FMO3, FMO5). Induction of CYP450 isozymes was evaluated in primary human hepatocytes incubated with omadacycline 1–100 μM and a substrate probe for 24 and 48 h. Inhibition of CYP450 isozymes was evaluated with pooled human microsomes at omadacycline concentrations of 1–50 μM and isozyme specific substrates at concentrations approximating the Km of each substrate. Isozymes evaluated included CYP 1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, and 3A4/5.Omadacycline did not induce CYP isozymes, and no or minimal (<40% of maximal positive control response) induction of their mRNAs was observed. Omadacycline demonstrated no significant inhibition of CYP isozyme activity. In addition, there was no time-dependent inhibition of omadacycline or its possible metabolites for CYP1A2 2C9, 2D6 or 3A4/5. |
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| Cell Assay | Omadacycline MIC90s for MRSA, VRE, and beta-hemolytic streptococci are 1.0 μg/mL, 0.25 μg/mL, and 0.5 μg/mL, correspondingly. For PRSP and H. influenzae, the corresponding omadacycline MIC90s are 0.25 μg/ml and 2.0 μg/mL. Omadacycline exhibits efficacy against organisms that exhibit both ribosomal protection and active tetracycline efflux, the two main mechanisms of resistance[1]. Omadacycline has little effect on the synthesis of DNA, RNA, or peptidoglycans, but it inhibits the synthesis of proteins. Furthermore, omadacycline exhibits enhanced binding, comparable to tigecycline, to the tetracycline binding site on the 30S subunit of the bacterial ribosome due to additional molecular interactions. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics | The pharmacokinetics of omadacycline are best described by a linear, three-compartment model following a zero-order intravenous infusion or first-order oral administration with transit compartments to account for delayed absorption. Omadacycline has a volume of distribution (Vd) ranging from 190 to 204 L, a terminal elimination half-life (t½) of 13.5-17.1 h, total clearance (CLT) of 8.8-10.6 L/h, and protein binding of 21.3% in healthy subjects. Oral bioavailability of omadacycline is estimated to be 34.5%. A single oral dose of 300 mg (bioequivalent to 100 mg IV) of omadacycline administered to fasted subjects achieved a maximum plasma concentration (Cmax) of 0.5-0.6 mg/L and an area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of 9.6-11.9 mg h/L. The free plasma area under concentration-time curve divided by the minimum inhibitory concentration (i.e., fAUC24h/MIC), has been established as the pharmacodynamic parameter predictive of omadacycline antibacterial efficacy. Several animal models including neutropenic murine lung infection, thigh infection, and intraperitoneal challenge model have documented the in vivo antibacterial efficacy of omadacycline. A phase II clinical trial on complicated skin and skin structure infection (cSSSI) and three phase III clinical trials on ABSSSI and CABP demonstrated the safety and efficacy of omadacycline. The phase III trials, OASIS-1 (ABSSSI), OASIS-2 (ABSSSI), and OPTIC (CABP), established non-inferiority of omadacycline to linezolid (OASIS-1, OASIS-2) and moxifloxacin (OPTIC), respectively. Omadacycline is currently approved by the FDA for use in treatment of ABSSSI and CABP. Phase II clinical trials involving patients with acute cystitis and acute pyelonephritis are in progress. Mild, transient gastrointestinal events are the predominant adverse effects associated with use of omadacycline. Based on clinical trial data to date, the adverse effect profile of omadacycline is similar to studied comparators, linezolid and moxifloxacin. Unlike tigecycline and eravacycline, omadacycline has an oral formulation that allows for step-down therapy from the intravenous formulation, potentially facilitating earlier hospital discharge, outpatient therapy, and cost savings. Omadacycline has a potential role as part of an antimicrobial stewardship program in the treatment of patients with infections caused by antibiotic-resistant and multidrug-resistant Gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA)] and Gram-negative pathogens. [https://pubmed.ncbi.nlm.nih.gov/31970713/] | ||
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of omadacycline during breastfeeding. It is unknown how much omadacycline is excreted into breastmilk, but the drug is only about 35% absorbed orally under optimal circumstances, and is probably less from milk because of its calcium content. The manufacturer states that breastfeeding is not recommended during treatment and for 4 days after the last dose. If an infant is breastfed, monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (e.g., thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis. As a theoretical precaution, avoid prolonged or repeat courses during nursing. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
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| References |
[1]. Omadacycline: A Newly Approved Antibacterial from the Class of Tetracyclines. Pharmaceuticals (Basel). 2019 Apr 21;12(2):63. [2]. In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Agents Chemother. 2014;58(2):1127-35. [3]. Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent. Drugs. 2020 Feb;80(3):285-313. [4]. Omadacycline: First Global Approval. Drugs. 2018 Dec;78(18):1931-1937. [5]. In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5247-53. [6]. Bioorg Med Chem.2016 Dec 15;24(24):6409-6419. |
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| Additional Infomation | See also: Omadacycline (annotation moved to); Omadacycline Tosylate (annotation moved to). |
Solubility Data
| Solubility (In Vitro) |
DMSO : 12.5 100 mg/mL ( 137.2 mM ) Water : 100 mg/mL Ethanol : 100 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: 50 mg/mL (68.60 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3720 mL | 6.8600 mL | 13.7201 mL | |
| 5 mM | 0.2744 mL | 1.3720 mL | 2.7440 mL | |
| 10 mM | 0.1372 mL | 0.6860 mL | 1.3720 mL |