cilastatin Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
enzyme inhibitors	640	82009-34-5

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: cilastatin cilastatin sodium cilastin cilastatin monosodium	A renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. Since the antibiotic, IMIPENEM, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene D4 to leukotriene E4. Molecular weight: 358.45 Formula: C16H26N2O5S CLOGP: 0.47 LIPINSKI: 0 HAC: 7 HDO: 4 TPSA: 129.72 ALOGS: -3.55 ROTB: 11 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

cilastatin
cilastatin sodium
cilastin
cilastatin monosodium

A renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. Since the antibiotic, IMIPENEM, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene D4 to leukotriene E4.

Molecular weight: 358.45
Formula: C16H26N2O5S
CLOGP: 0.47
LIPINSKI: 0
HAC: 7
HDO: 4
TPSA: 129.72
ALOGS: -3.55
ROTB: 11

Status: OFP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

Dose	Unit	Route
2	g	P

ADMET properties:

Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	3	Benet LZ, Broccatelli F, Oprea TI
S (Water solubility)	25 mg/mL	Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine)	70 %	Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose)	59.78 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
Vd (Volume of distribution)	0.15 L/kg	Lombardo F, Berellini G, Obach RS
CL (Clearance)	2.30 mL/min/kg	Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma)	0.60 %	Lombardo F, Berellini G, Obach RS
t_half (Half-life)	0.86 hours	Lombardo F, Berellini G, Obach RS

Approvals:

Date	Agency	Company	Orphan
Nov. 26, 1985	FDA	MERCK

FDA Adverse Event Reporting System (Female)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Seizure	241.76	82.10	73	657	24393	2332962
Drug ineffective	83.10	82.10	52	678	101572	2255783

FDA Adverse Event Reporting System (Male)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Seizure	260.12	69.31	90	905	20351	1725435
Pathogen resistance	186.80	69.31	38	957	1051	1744735
Drug ineffective	158.72	69.31	89	906	63712	1682074
Sepsis	110.73	69.31	48	947	19390	1726396
Septic shock	99.51	69.31	35	960	8074	1737712
Multiple organ dysfunction syndrome	98.76	69.31	36	959	9206	1736580
Toxic epidermal necrolysis	88.26	69.31	24	971	2347	1743439
Drug resistance	80.92	69.31	24	971	3206	1742580
Respiratory failure	79.75	69.31	35	960	14470	1731316
Thrombocytopenia	78.74	69.31	39	956	21210	1724576
Pyrexia	76.33	69.31	50	945	46350	1699436
Toxic skin eruption	69.77	69.31	19	976	1864	1743922

Pharmacologic Action:

Source	Code	Description
ATC	J01DH51	ANTIINFECTIVES FOR SYSTEMIC USE ANTIBACTERIALS FOR SYSTEMIC USE OTHER BETA-LACTAM ANTIBACTERIALS Carbapenems
FDA MoA	N0000175513	Dipeptidase Inhibitors
FDA EPC	N0000175514	Renal Dehydropeptidase Inhibitor
MeSH PA	D004791	Enzyme Inhibitors
MeSH PA	D011480	Protease Inhibitors

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID	DOID
Bacterial septicemia	indication	10001005	DOID:0040085
Infection of skin AND/OR subcutaneous tissue	indication	19824006
Pneumonia due to Streptococcus	indication	34020007
Peritonitis	indication	48661000
Lower respiratory tract infection	indication	50417007
Pneumonia due to Escherichia coli	indication	51530003
Bacterial pneumonia	indication	53084003	DOID:874
Haemophilus influenzae pneumonia	indication	70036007
Abdominal abscess	indication	75100008
Endometritis	indication	78623009	DOID:1002
Infection of bone	indication	111253001
Female genital tract infection	indication	125585007
Infectious disease of abdomen	indication	128070006
Bacterial infection due to Klebsiella pneumoniae	indication	186435004
Bacterial endocarditis	indication	301183007
Bacterial urinary infection	indication	312124009
Infectious disorder of joint	indication	363162000
Acute exacerbation of chronic bronchitis	indication	425748003
Inflammatory Disease of Female Pelvic Organs	indication
Enterobacter Pneumonia	indication
Diabetic Foot Infection	indication
Gram-Negative Aerobic Bacillary Pneumonia	indication
Pyrexia of unknown origin	off-label use	7520000
Inhalational anthrax	off-label use	11389007
Cutaneous anthrax	off-label use	84980006	DOID:7426
Gastrointestinal anthrax	off-label use	111798006	DOID:13386
Infection by Campylobacter fetus	off-label use	111835002
Gas gangrene caused by clostridium perfringens	off-label use	266093005
Anthrax	off-label use	409498004	DOID:7427
Melioidosis	off-label use	428111003	DOID:5052
Clostridium Perfringens Empyema	off-label use
Pseudomonas Respiratory Tract Infection in Cystic Fibrosis	off-label use
Kidney disease	contraindication	90708001	DOID:557
Seizure disorder	contraindication	128613002
Lesion of brain	contraindication	301766008
Pseudomembranous enterocolitis	contraindication	397683000

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	2.08	acidic
pKa2	3.82	acidic
pKa3	12.31	acidic
pKa4	9.35	Basic

Orange Book patent data (new drug applications)

Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Patent number	Patent expiration date	Patent use
EQ 500MG BASE/VIAL	RECARBRIO	MSD MERCK CO	N212819	July 16, 2019	RX	POWDER	INTRAVENOUS	8487093	Nov. 19, 2029	TREATMENT OF COMPLICATED INTRA-ABDOMINAL INFECTIONS (CIAI)
EQ 500MG BASE/VIAL	RECARBRIO	MSD MERCK CO	N212819	July 16, 2019	RX	POWDER	INTRAVENOUS	8487093	Nov. 19, 2029	TREATMENT OF COMPLICATED URINARY TRACT INFECTIONS, INCLUDING PYELONEPHRITIS (CUTI)

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Mechanism action	Bioact source	MoA source
Dipeptidase 1	Enzyme	P16444	DPEP1_HUMAN	INHIBITOR	Ki	6.96		WOMBAT-PK	CHEMBL
Dipeptidase 1	Enzyme		DPEP1_PIG		Ki	6.96		CHEMBL

External reference:

ID	Source
4019679	VUID
N0000147771	NUI
C0008777	UMLSCUI
D02194	KEGG_DRUG
141A6AMN38	UNII
5457	INN_ID
81129-83-1	SECONDARY_CAS_RN
422591002	SNOMEDCT_US
2540	RXNORM
96058005	SNOMEDCT_US
d04402	MMSL
4019679	VANDF
004539	NDDF
CHEMBL766	ChEMBL_ID
CIL	PDB_CHEM_ID
DB01597	DRUGBANK_ID
CHEBI:3697	CHEBI
5166	IUPHAR_LIGAND_ID
CHEMBL1201057	ChEMBL_ID
D015377	MESH_DESCRIPTOR_UI
6435415	PUBCHEM_CID

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
PRIMAXIN	HUMAN PRESCRIPTION DRUG LABEL	2	0006-3514	INJECTION, POWDER, FOR SOLUTION	250 mg	INTRAVENOUS	NDA	16 sections
PRIMAXIN	HUMAN PRESCRIPTION DRUG LABEL	2	0006-3516	INJECTION, POWDER, FOR SOLUTION	500 mg	INTRAVENOUS	NDA	16 sections
PRIMAXIN	HUMAN PRESCRIPTION DRUG LABEL	2	0006-3551	INJECTION, POWDER, FOR SOLUTION	250 mg	INTRAVENOUS	ANDA	16 sections
PRIMAXIN	HUMAN PRESCRIPTION DRUG LABEL	2	0006-3552	INJECTION, POWDER, FOR SOLUTION	500 mg	INTRAVENOUS	ANDA	16 sections
RECARBRIO	HUMAN PRESCRIPTION DRUG LABEL	1	0006-3856	INJECTION, POWDER, FOR SOLUTION	500 mg	INTRAVENOUS	NDA	17 sections
Imipenem and Cilastatin	HUMAN PRESCRIPTION DRUG LABEL	2	63323-322	INJECTION, POWDER, FOR SOLUTION	500 mg	INTRAVENOUS	ANDA	16 sections
Imipenem and Cilastatin	HUMAN PRESCRIPTION DRUG LABEL	2	63323-349	INJECTION, POWDER, FOR SOLUTION	250 mg	INTRAVENOUS	ANDA	16 sections