 Chemical Structure.png)
Oritavancin diphosphate (LY-333328; LY 333328; LY333328; trade name Orbactiv), the diphosphate of Oritavancin, is a semisynthetic lipoglycopeptide analog of vancomycin approved in 2014 by FDA as an antibiotic for the treatment of serious Gram-positive bacterial infections.
Physicochemical Properties
| Molecular Formula | C86H103CL3N10O34P2 |
| Molecular Weight | 1989.0912 |
| Exact Mass | 1986.517 |
| Elemental Analysis | C, 51.93; H, 5.22; Cl, 5.35; N, 7.04; O, 27.35; P, 3.11 |
| CAS # | 192564-14-0 |
| Related CAS # | Oritavancin;171099-57-3 |
| PubChem CID | 53297457 |
| Appearance | White to off-white solid powder |
| LogP | 6.855 |
| Hydrogen Bond Donor Count | 26 |
| Hydrogen Bond Acceptor Count | 37 |
| Rotatable Bond Count | 19 |
| Heavy Atom Count | 135 |
| Complexity | 3750 |
| Defined Atom Stereocenter Count | 22 |
| SMILES | ClC1=C2C([H])=C([H])C(=C1[H])[C@]([H])([C@@]1([H])C(N([H])[C@]([H])(C(=O)O[H])C3C([H])=C(C([H])=C(C=3C3=C(C([H])=C([H])C(=C3[H])[C@]([H])(C(N1[H])=O)N([H])C([C@@]1([H])C3=C([H])C(=C(C(=C3[H])O2)O[C@@]2([H])[C@@]([H])([C@]([H])([C@@]([H])([C@@]([H])(C([H])([H])O[H])O2)O[H])O[H])O[C@@]2([H])C([H])([H])[C@@](C([H])([H])[H])([C@]([H])([C@]([H])(C([H])([H])[H])O2)O[H])N([H])C([H])([H])C2C([H])=C([H])C(C3C([H])=C([H])C(=C([H])C=3[H])Cl)=C([H])C=2[H])OC2C([H])=C([H])C([C@]([H])([C@]([H])(C(N([H])[C@@]([H])(C([H])([H])C(N([H])[H])=O)C(N1[H])=O)=O)N([H])C([C@@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([H])([H])[H])=O)O[H])=C([H])C=2Cl)=O)O[H])O[H])O[H])=O)O[C@@]1([H])C([H])([H])[C@@](C([H])([H])[H])([C@]([H])([C@]([H])(C([H])([H])[H])O1)O[H])N([H])[H].P(=O)(O[H])(O[H])O[H].P(=O)(O[H])(O[H])O[H] |
| InChi Key | PWTROOMOPLCZHB-BHYQHFGMSA-N |
| InChi Code | InChI=1S/C86H97Cl3N10O26.2H3O4P/c1-35(2)22-51(92-7)77(110)98-67-69(105)42-15-20-55(49(88)24-42)120-57-26-44-27-58(73(57)125-84-74(71(107)70(106)59(34-100)122-84)124-62-32-86(6,76(109)37(4)119-62)93-33-38-8-10-39(11-9-38)40-12-17-45(87)18-13-40)121-56-21-16-43(25-50(56)89)72(123-61-31-85(5,91)75(108)36(3)118-61)68-82(115)97-66(83(116)117)48-28-46(101)29-54(103)63(48)47-23-41(14-19-53(47)102)64(79(112)99-68)96-80(113)65(44)95-78(111)52(30-60(90)104)94-81(67)114;2*1-5(2,3)4/h8-21,23-29,35-37,51-52,59,61-62,64-72,74-76,84,92-93,100-103,105-109H,22,30-34,91H2,1-7H3,(H2,90,104)(H,94,114)(H,95,111)(H,96,113)(H,97,115)(H,98,110)(H,99,112)(H,116,117);2*(H3,1,2,3,4)/t36-,37-,51+,52-,59+,61-,62-,64+,65+,66-,67+,68-,69+,70+,71-,72+,74+,75-,76-,84-,85-,86-;;/m0../s1 |
| Chemical Name | (4R)-22-O-(3-Amino-2,3,6-trideoxy-3-C-methyl-α-L-arabinohexopyranosyl)-N3-(p-(p-chlorophenyl)benzyl)vancomycin diphosphate |
| Synonyms | LY333328; Oritavancin; Oritavancin diphosphate; LY-333328; LY 333328; trade name: Orbactiv. Oritavancin diphosphate; 192564-14-0; Orbactiv; LY333328 diphosphate; oritavancin phosphate; Nuvocid; LY 333328 diphosphate; Kimyrsa; |
| 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, avoid exposure to moisture. |
| 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 | Glycopeptide; macrolides antibiotic/bactericidal; cell wall synthesis |
| ln Vitro |
Oritavancin, a semisynthetic lipoglycopeptide with activity against gram-positive bacteria, has multiple mechanisms of action, including the inhibition of cell wall synthesis and the perturbation of the membrane potential. [1] Both oritavancin and vancomycin achieved 99.9% (3-log) kill, with oritavancin achieving the limit of detection (10(2) CFU/ml) within 1 h and vancomycin achieving this limit at 24 h for both isolates. Detection of resistance was not observed for oritavancin or vancomycin during the 48-h experiments. The key pharmacodynamic parameter for oritavancin has not been well defined. In our experiment, the ratios of the area under the curve from 0 to 24 h to the MIC of oritavancin, oritavancin plus albumin, and vancomycin for both isolates were greater than 944.5, and the ratios of the maximum concentration of drug in serum to the MIC ranged from 73.7 to 7188.5. T>MIC was 100% for oritavancin and vancomycin for both isolates. Oritavancin is a unique and potent antimicrobial that warrants further investigation against multidrug-resistant S. pneumoniae[2]. |
| ln Vivo | In postexposure prophylaxis dose-ranging studies, a single intravenous (i.v.) dose of oritavancin of 5, 15, or 50 mg/kg 24 h after a challenge with 50 to 75 times the median lethal dose of Ames strain spores provided 40, 70, and 100% proportional survival, respectively, at 30 days postchallenge. Untreated animals died within 4 days of challenge, whereas 90% of control animals receiving ciprofloxacin at 30 mg/kg intraperitoneally twice daily for 14 days starting 24 h after challenge survived. Oritavancin demonstrated significant activity post symptom development; a single i.v. dose of 50 mg/kg administered 42 h after challenge provided 56% proportional survival at 30 days. In a preexposure prophylaxis study, a single i.v. oritavancin dose of 50 mg/kg administered 1, 7, 14, or 28 days before lethal challenge protected 90, 100, 100, and 20% of mice at 30 days; mice treated with ciprofloxacin 24 h or 24 and 12 h before challenge all died within 5 days. Efficacy in pre- and postexposure models of inhalation anthrax, together with a demonstrated low propensity to engender resistance, promotes further study of oritavancin pharmacokinetics and efficacy in nonhuman primate models[3]. |
| Enzyme Assay |
Susceptibility of B. anthracis strains to oritavancin as measured by broth microdilution. [3] Oritavancin MICs were determined by broth microdilution in 96-well plates according to guidelines of the Clinical and Laboratory Standards Institute. As recommended in guideline M100-S18, polysorbate 80 was included at a final concentration of 0.002% throughout drug dissolution and all steps of the assay to minimize oritavancin binding to surfaces. To determine the impact, if any, of polysorbate 80 upon oritavancin MICs for B. anthracis, a parallel broth microdilution assay was conducted in which oritavancin was dissolved in water and drug dilutions were prepared without polysorbate 80. Quality control of oritavancin dilutions was established by using S. aureus ATCC 29213 with polysorbate 80 at 0.002% throughout; an acceptable range of oritavancin MICs against this strain is 0.015 to 0.12 μg/ml. Titration of polysorbate 80 in oritavancin MIC test. [1] To determine the polysorbate 80 concentration dependence of the oritavancin MICs, broth microdilution susceptibility tests with S. aureus ATCC 29213 as an indicator strain were performed according to the CLSI M7-A7 methodology, except that various test concentrations of polysorbate 80 were included at the drug dissolution step and were maintained at the test concentration onwards.[1] Order of addition of polysorbate 80 in oritavancin MIC test. [1] To determine whether the order of addition of polysorbate 80 affected the oritavancin MICs, broth microdilution susceptibility tests were performed with S. aureus ATCC 29213 as an indicator strain, in which oritavancin was either dissolved in 0.002% polysorbate 80 and diluted and assayed by maintaining polysorbate 80 at 0.002% or dissolved and diluted in water and then assayed by adding inoculum with or without polysorbate 80. When polysorbate 80 was present, it was added at a final concentration of 0.002%, as described in the CLSI guidelines for dalbavancin. |
| Cell Assay |
In vitro pharmacodynamic model. [2] The in vitro pharmacodynamic model consists of a 250-ml one-compartment glass chamber with ports for the addition and removal of the THB with 0.5% yeast extract with or without albumin, injection of antibiotics, and removal of samples. Prior to each experiment, colonies from an overnight growth of bacteria on TSA plates with 5% SB were added to THB with 0.5% yeast extract to obtain a concentration of 106 CFU/ml. Fresh stock solutions of oritavancin and vancomycin were prepared daily and were stored at 2 to 8°C between dose administration times. Experimental regimens simulated antibiotic concentrations achieved in human plasma. Vancomycin was administered at a dose of 1 g every 12 h (four doses given) to achieve a peak concentration in serum (Cmax) of 30 μg/ml and a trough concentration of 7.5 μg/ml. To achieve targeted concentrations of oritavancin in plasma during the first 48 h of dosing in humans, oritavancin was administered at a loading dose of 5 mg/kg of body weight at 0 h, followed by 4 mg/kg at 24 h, to achieve a peak concentration of 100 μg/ml and 24-h trough concentration of 15 μg/ml. Each antibiotic was administered as a bolus into the models over 30 s using a hypodermic syringe. Fresh medium (SMHB) was continuously supplied and removed from the model along with the drug via a peristaltic pump set to simulate the half-lives (t1/2s) of vancomycin (6.5 h) and oritavancin (t1/2 at α phase [t1/2α] = 2 h); the pump ran in this manner for 8 h after dosing and then was changed to simulate a t1/2 of 12.3 h for the remaining 16 h of the 24 h dosing period. Each model apparatus was placed in a water bath and maintained at 37°C for the entire 48 h study period. The pharmacodynamic model experiments were performed in duplicate, simultaneously, in order to ensure reproducibility. |
| Animal Protocol |
Oritavancin pharmacokinetics and dosing determinations.[3] A pharmacokinetics study was performed with mice to compare oritavancin exposures in plasma after the administration of a single dose of oritavancin by the intravenous (i.v.) and intraperitoneal (i.p.) routes. Because multiple doses of test and control agents are typically required in the mouse model of inhalation anthrax for effective postexposure prophylaxis and treatment, the i.p. route is the preferred route of administration during therapy. However, the possibility of infrequent and even single i.v. administration of oritavancin has been established in efficacy studies in a neutropenic mouse model of S. aureus thigh infection, in an immunocompetent mouse model of Streptococcus pneumoniae infection, and in a rat model of S. aureus granuloma pouch infection. Mice (female CD-1; body weight, 19 to 21 g) received a single bolus dose of oritavancin of 32 mg/kg in dosing formulation (see below) either i.v. or i.p., and blood was collected by cardiac puncture (n = 3 mice/time point). Levels of oritavancin (total drug) in plasma were determined by a validated liquid chromatography-mass spectrometry method. Free oritavancin levels were calculated by using a value of 93.6% bound in mouse serum (W. Craig, unpublished data). Pharmacokinetic parameters were calculated by using WinNonlin software). All parameters were calculated by using a noncompartmental model.[3] Determination of efficacy of oritavancin in the mouse inhalation anthrax model.[3] (i) Preparation of oritavancin dosing formulation. Oritavancin for injection was formulated by dissolving oritavancin diphosphate; assay potency [volatile-free basis], 84.9%) in 5% dextrose in water to the appropriate concentration, followed by sterile filtration. Due to the saturable binding of oritavancin (2) and its near-quantitative loss to filter membranes at low drug concentrations (e.g., below 10 μg/ml), oritavancin concentrations were maintained above 1 mg/ml during dissolution and filtration before dilution and administration. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because oritavancin is poorly absorbed orally, it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. Monitor the infant for possible effects on the gastrointestinal tract, such as diarrhea, vomiting, and candidiasis (e.g., thrush, diaper rash). However, because there is no published experience with oritavancin during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ 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. |
| References |
[1]. Effect of polysorbate 80 on oritavancin binding to plastic surfaces: implications for susceptibility testing. Antimicrob Agents Chemother. 2008 May;52(5):1597-1603. [2]. Activity of oritavancin (LY333328), an investigational glycopeptide, compared to that of vancomycin against multidrug-resistant Streptococcus pneumoniae in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2001 Mar;45(3):706-9. [3]. Efficacy of oritavancin in a murine model of Bacillus anthracis spore inhalation anthrax. Antimicrob Agents Chemother. 2008 Sep;52(9):3350-7. |
| Additional Infomation |
Oritavancin bisphosphate is a phosphate salt obtained by combining oritavancin with two molar equivalents of phosphoric acid. Used for the treatment of acute bacterial skin and skin structure infections caused or suspected to be caused by susceptible isolates of designated Gram-positive microorganisms. It has a role as an antibacterial drug. It contains an oritavancin. See also: Oritavancin (has active moiety). Drug Indication Treatment of acute bacterial skin and skin structure infections |
Solubility Data
| Solubility (In Vitro) |
DMSO : 41.67~100 mg/mL ( 20.95~50.27 mM ) Water : ~50 mg/mL (~25.14 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (1.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (1.05 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (1.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (1.05 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.5027 mL | 2.5137 mL | 5.0274 mL | |
| 5 mM | 0.1005 mL | 0.5027 mL | 1.0055 mL | |
| 10 mM | 0.0503 mL | 0.2514 mL | 0.5027 mL |