ORITAVANCIN DIPHOSPHATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C86H97Cl3N10O26.2H3O4P
Molecular Weight	1989.091
Optical Activity	UNSPECIFIED
Defined Stereocenters	22 / 22
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OP(O)(O)=O.OP(O)(O)=O.[H][C@@]1(C[C@](C)(NCC2=CC=C(C=C2)C3=CC=C(Cl)C=C3)[C@@H](O)[C@H](C)O1)O[C@@H]4[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]4OC5=C6OC7=CC=C(C=C7Cl)[C@@H](O)[C@@H](NC(=O)[C@@H](CC(C)C)NC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@]8([H])C(C=C5OC9=C(Cl)C=C(C=C9)[C@@H](O[C@@]%10([H])C[C@](C)(N)[C@@H](O)[C@H](C)O%10)[C@]%11([H])NC(=O)[C@]([H])(NC8=O)C%12=CC=C(O)C(=C%12)C%13=C(C=C(O)C=C%13O)[C@]([H])(NC%11=O)C(O)=O)=C6

InChI

InChIKey=PWTROOMOPLCZHB-BHYQHFGMSA-N

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

HIDE SMILES / InChI

Description
Sources: http://www.orbactiv.com/pdfs/orbactiv-prescribing-information.pdf | http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003785/WC500186347.pdf
Curator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB04911 | https://www.ncbi.nlm.nih.gov/pubmed/26831328

Oritavancin is an glycopeptide antibiotic with bactericidal activity effective in treating infections caused by Gram-positive organisms. It treats complicated skin and skin structure infections. This drug demonstrates similar activity to vancomycin, but it has stronger activity against Staphylococcus and Enterococcus. The pharmacokinetics and pharmacodynamics of oritavancin appear to be favourable and once-daily dosing is likely. The incidence of multi-drug resistant bacteria is increasing and explorations into additional treatment options are essential. Oritavancin is marketed under the brand name Orbactiv. Orbactiv is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections caused or suspected to be caused by susceptible isolates of designated Gram-positive microorganisms. Oritavancin has the following mechanism of action: 1) Inhibition of the transglycosylation (polymerisation) step of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors 2) Inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging segments of the cell wall 3) Disruption of bacterial membrane integrity, leading to depolarisation, increased permeability and rapid cell death.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Staphylococcus aureus 67 Target ID: CHEMBL352 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26831328	Inhibitor 8297
Streptococcus pyogenes 6 Target ID: CHEMBL356 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26831328	Inhibitor 8297
Enterococcus faecium 5 Target ID: CHEMBL357 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26831328	Inhibitor 8297
Peptidoglycan 6 Target ID: CHEMBL3041361 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute bacterial skin and skin structure infection 16 Sources: http://www.orbactiv.com/pdfs/orbactiv-prescribing-information.pdf	Curative		Approved 8429	ORBACTIV Approved Use ORBACTIV is a lipoglycopeptide antibacterial drug indicated for the treatment of adult patients with acute bacterial skin and skin structure infections caused or suspected to be caused by susceptible isolates of designated Gram-positive microorganisms. (1.1) To reduce the development of drug-resistant bacteria and maintain the effectiveness of ORBACTIV and other antibacterial drugs, ORBACTIV should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.2) 1.1 Acute Bacterial Skin and Skin Structure Infections ORBACTIV® (oritavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin–resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis (vancomycin-susceptible isolates only). 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ORBACTIV and other antibacterial drugs, ORBACTIV should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Launch Date 2014

C_max

Value	Dose	Co-administered	Analyte	Population
138 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf	1200 mg single, intravenous dose: 1200 mg route of administration: Intravenous experiment type: SINGLE co-administered:		[NO STEREO] ORITAVANCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
2800 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf	1200 mg single, intravenous dose: 1200 mg route of administration: Intravenous experiment type: SINGLE co-administered:		[NO STEREO] ORITAVANCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
13.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf	1200 mg single, intravenous dose: 1200 mg route of administration: Intravenous experiment type: SINGLE co-administered:		[NO STEREO] ORITAVANCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
15% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf	1200 mg single, intravenous dose: 1200 mg route of administration: Intravenous experiment type: SINGLE co-administered:		[NO STEREO] ORITAVANCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1200 mg single, intravenous Recommended Dose: 1200 mg Route: intravenous Route: single Dose: 1200 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf Page: 5	unhealthy, 18-89 years n = 976 Health Status: unhealthy Condition: acute bacterial skin Age Group: 18-89 years Sex: M+F Population Size: 976 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf Page: 5	Disc. AE: Cellulitis, Osteomyelitis... AEs leading to discontinuation/dose reduction: Cellulitis (0.4%) Osteomyelitis (0.3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf Page: 5
1200 mg 1 times / day multiple, intravenous (median) Recommended Dose: 1200 mg, 1 times / day Route: intravenous Route: multiple Dose: 1200 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000MedR.pdf Page: 111	unhealthy, adult n = 976 Health Status: unhealthy Condition: acute bacterial skin Age Group: adult Sex: M+F Population Size: 976 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000MedR.pdf Page: 111	Disc. AE: Mouth ulceration, Nausea... AEs leading to discontinuation/dose reduction: Mouth ulceration (1 patient) Nausea (1 patient) Rectal haemorrhage (1 patient) Vomiting (1 patient) Chest discomfort (1 patient) Infusion site extravasation (1 patient) Infusion site pain (1 patient) Infusion site phlebitis (2 patients) Infusion site thrombosis (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000MedR.pdf Page: 111
1200 mg 1 times / day multiple, intravenous (median) Recommended Dose: 1200 mg, 1 times / day Route: intravenous Route: multiple Dose: 1200 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000MedR.pdf Page: 112	unhealthy, adult n = 976 Health Status: unhealthy Condition: acute bacterial skin Age Group: adult Sex: M+F Population Size: 976 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000MedR.pdf Page: 112	Disc. AE: Drug hypersensitivity, Urine ketone body present... AEs leading to discontinuation/dose reduction: Drug hypersensitivity (1 patient) Urine ketone body present (1 patient) Hyperglycaemia (1 patient) Tenosynovitis (1 patient) Somnolence (1 patient) Erythema multiforme (1 patient) Leukocytoclastic vasculitis (1 patient) Pruritus (2 patients) Rash (1 patient) Rash macular (1 patient) Urticaria (1 patient) Hypotension (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000MedR.pdf Page: 112

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781	inhibitor 1767	inducer 97 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1478 P-gp 1461 CYP1A2 1524 CYP3A 214 CYP2B6 810	P-gp 1537

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	weak	yes (co-administration study) Comment: The effect of oritavancin on omeprazole, a CYP2C19 substrate, was determined from the omeprazole/5-OH omeprazole ratio in the plasma at 2 hours. There was an increase of 15% in this metabolic ratio. The Day 1/Day-4 geometric mean ratio (point estimate) and 90% CI was 1.155 (0.957, 1.395), suggesting that oritavancin may be a weak inhibitor of CYP2C19. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=40 Page: 40.0
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	weak	yes (co-administration study) Comment: In the overall population (N=16), plasma Swarfarin AUC0-inf values increased by 31%. The Day 1/Day-4 geometric mean ratio (point estimate) and 90% CI was 1.319 (1.294, 1.345). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=40 Page: 40.0
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=46 Page: 46.0	yes [IC50 16 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=46 Page: 46.0	yes [IC50 40.5 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=46 Page: 46.0	yes
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=46 Page: 46.0	yes
CYP2D6 1891	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes	yes (co-administration study) Comment: The effect of oritavancin on dextromethorphan, a CYP2D6 substrate, was determined from the dextromethorphan over dextrorphan molar ratio in urine samples collected over a 12-hour interval after dosing. The Day 1/Day -4 geometric mean ratio (point estimate) and 90% CI (N=13 subjects) was 0.692 (0.431, 1.110). These findings indicate a 31% decrease in the urinary dextromethorphan/dextrorphan ratio, and that oritavancin is a weak inducer of CYP2D6. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=40 Page: 40.0
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes	yes (co-administration study) Comment: In the presence of oritavancin (Day 1) the AUC0-inf of midazolam was decreased by 18% and the CL/F was increased by 24%. The Day 1/Day -4 geometric mean ratio (point estimate) and 90% CI for CL/F was 1.239 (1.135, 1.353). The 24% increase in the midazolam CL/F and decrease (18%) in the midazolam AUC0-inf indicates that oritavancin is a weak inducer of CYP3A4. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=40 Page: 40.0

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206334Orig1s000ClinPharmR.pdf#page=26 Page: 26.0

Sourcing

Vendor/Aggregator	ID	URL
AbMole Bioscience	M4885	http://www.abmole.com/products/oritavancin.html
BLD Pharm	BD764477	http://www.bldpharm.com/products/171099-57-3.html
Clearsynth	CS-L-00125	https://www.clearsynth.com/en/CSL00125.html
Excenen	EX-A2372	https://www.excenen.com/searchresultlist.php?id=171099-57-3
MetabolomicsWorkbench	70998	http://www.metabolomicsworkbench.org/data/StructureData.php?RegNo=70998
MolPort	MolPort-006-170-024	https://www.molport.com/shop/molecule-link/MolPort-006-170-024
MuseChem	I011842	https://www.musechem.com/product/I011842.html
Smolecule	S005579	http://www.smolecule.com/products/s005579
THE BioTek	bt-254938	https://www.thebiotek.com/product/inhibitors/bt-254938
eNovation Chemicals	D567301	https://www.enovationchem.com/ProductDetails.asp?ProductID=D567301

PubMed

Title	Date	PubMed
Intracellular activity of antibiotics in a model of human THP-1 macrophages infected by a Staphylococcus aureus small-colony variant strain isolated from a cystic fibrosis patient: pharmacodynamic evaluation and comparison with isogenic normal-phenotype and revertant strains.	2009 Apr	19188393

Patents

Sample Use Guides

In Vivo Use Guide

A 1200 mg single dose is administered by intravenous infusion over 3 hours.

Route of Administration: Intravenous

In Vitro Use Guide

The MIC50 and MIC90 for oritavancin against vancomycin-susceptible E. faecalis were 0.015 and 0.03 mg/L and E. faecium of

Name

Type

Language

ORITAVANCIN DIPHOSPHATE

Official Name

English

KIMYRSA

Brand Name

English

NUVOCID

Brand Name

English

ORITAVANCIN DIPHOSPHATE [USAN]

Common Name

English

LY333328 DIPHOSPHATE

Code

English

ORITAVANCIN DIPHOSPHATE [MI]

Common Name

English

VANCOMYCIN, 22-O-(3-AMINO-2,3,6-TRIDEOXY-3-C-METHYL-.ALPHA.-L-ARABINO-HEXOPYRANOSYL)-N3''-((4'-CHLORO(1,1'-BIPHENYL)-4-YL)METHYL)-, (4''R)-, PHOSPHATE (1:2)

Systematic Name

English

VANCOMYCIN, 22-O-(3-AMINO-2,3,6-TRIDEOXY-3-C-METHYL-.ALPHA.-L-ARABINO-HEXOPYRANOSYL)-N3''-((4'-CHLORO(1,1'-BIPHENYL)-4-YL)METHYL)-, (4''R)-, PHOSPHATE (1:2) (SALT)

Systematic Name

English

ORITAVANCIN DIPHOSPHATE [ORANGE BOOK]

Common Name

English

LY-333328 DIPHOSPHATE

Code

English

Oritavancin diphosphate [WHO-DD]

Common Name

English

ORITAVANCIN PHOSPHATE [MART.]

Common Name

English

ORITAVANCIN DIPHOSPHATE [VANDF]

Common Name

English

ORBACTIV

Brand Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

ORBACTIV (AUTHORIZED SOFT TISSUE INFECTIONS)