DICHLORO-1,2-DIAMINOCYCLOHEXANE PLATINUM COMPLEX

First approved in 2002

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021759lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/19255091

Oxaliplatin (brand name Eloxatin), a new generation of platinum derivatives discovered by Prof Kidani in 1976 at Nagoya University in Japan, was licensed-in and developed by Debiopharm. Eloxatin is typically administered in combination with fluorouracil and leucovorin for the adjuvant treatment of stage III colon cancer and for the treatment of advanced carcinoma of the colon or rectum. Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo 1,2-diaminocyclohexane (DACH) platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 282 Target ID: CHEMBL2311221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19255091	Crosslinking Agent 83

Conditions

Condition	Modality	Targets	Highest Phase	Product
Colon cancer 66 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021759lbl.pdf	Primary		Approved 8583	ELOXATIN Approved Use Oxaliplatin, used in combination with infusional 5-fluorouracil/leucovorin, is indicated for: •adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. •treatment of advanced colorectal cancer. Oxaliplatin injection is a platinum-based drug used in combination with infusional 5-fluorouracil/leucovorin, which is indicated for: •adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. (1) •treatment of advanced colorectal cancer. (1) Launch Date 2002
Carcinoma of the colon or rectum 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021759lbl.pdf	Primary		Approved 8583	ELOXATIN Approved Use Oxaliplatin, used in combination with infusional 5-fluorouracil/leucovorin, is indicated for: •adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. •treatment of advanced colorectal cancer. Oxaliplatin injection is a platinum-based drug used in combination with infusional 5-fluorouracil/leucovorin, which is indicated for: •adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. (1) •treatment of advanced colorectal cancer. (1) Launch Date 2002

C_max

Value	Dose	Co-administered	Analyte	Population
4.66 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16395593	130 mg/m² 1 times / 3 weeks steady-state, intravenous dose: 130 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		OXALIPLATIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
205.75 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16395593	130 mg/m² 1 times / 3 weeks steady-state, intravenous dose: 130 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		OXALIPLATIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
42.84 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16395593	130 mg/m² 1 times / 3 weeks steady-state, intravenous dose: 130 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		OXALIPLATIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
10% DRUG LABEL https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB00526.pdf?1265922796			PLATINUM plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
130 mg/m2 single, intravenous Dose: 130 mg/m2 Route: intravenous Route: single Dose: 130 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/33131450	unhealthy, 56 years Health Status: unhealthy Age Group: 56 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/33131450	Disc. AE: Hypersensitivity reaction... AEs leading to discontinuation/dose reduction: Hypersensitivity reaction (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/33131450
135 mg/m2 1 times / 4 weeks multiple, intravenous Dose: 135 mg/m2, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 135 mg/m2, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	unhealthy, 57 years (range: 26-81 years) Health Status: unhealthy Age Group: 57 years (range: 26-81 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	DLT: Neurotoxicity... Dose limiting toxicities: Neurotoxicity (50%) Sources: https://pubmed.ncbi.nlm.nih.gov/2295116
150 mg/m2 1 times / 4 weeks multiple, intravenous Dose: 150 mg/m2, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 150 mg/m2, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	unhealthy, 57 years (range: 26-81 years) Health Status: unhealthy Age Group: 57 years (range: 26-81 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	DLT: Neurotoxicity... Dose limiting toxicities: Neurotoxicity (64%) Sources: https://pubmed.ncbi.nlm.nih.gov/2295116
175 mg/m2 1 times / 4 weeks multiple, intravenous Dose: 175 mg/m2, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 175 mg/m2, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	unhealthy, 57 years (range: 26-81 years) Health Status: unhealthy Age Group: 57 years (range: 26-81 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	DLT: Neurotoxicity... Dose limiting toxicities: Neurotoxicity (71%) Sources: https://pubmed.ncbi.nlm.nih.gov/2295116
200 mg/m2 1 times / 4 weeks multiple, intravenous Dose: 200 mg/m2, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 200 mg/m2, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	unhealthy, 57 years (range: 26-81 years) Health Status: unhealthy Age Group: 57 years (range: 26-81 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	DLT: Neurotoxicity... Dose limiting toxicities: Neurotoxicity (100%) Sources: https://pubmed.ncbi.nlm.nih.gov/2295116
55 mg/m2 multiple, intravenous Dose: 55 mg/m2 Route: intravenous Route: multiple Dose: 55 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/33012678/	unhealthy, 58 years Health Status: unhealthy Age Group: 58 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/33012678/	Disc. AE: Thrombocytopenia... AEs leading to discontinuation/dose reduction: Thrombocytopenia (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/33012678/
150 mg/m2 1 times / 3 weeks single, intravenous Dose: 150 mg/m2, 1 times / 3 weeks Route: intravenous Route: single Dose: 150 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	unhealthy, 60 years (range: 33-75 years) Health Status: unhealthy Age Group: 60 years (range: 33-75 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	Disc. AE: Diarrhoea... AEs leading to discontinuation/dose reduction: Diarrhoea (grade 3, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/8343268
725 mg/m2 single, intravenous Dose: 725 mg/m2 Route: intravenous Route: single Dose: 725 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	unhealthy, 60 years (range: 33-75 years) Health Status: unhealthy Age Group: 60 years (range: 33-75 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	Disc. AE: Peripheral sensory neuropathy... AEs leading to discontinuation/dose reduction: Peripheral sensory neuropathy (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/8343268
900 mg/m2 single, intravenous Dose: 900 mg/m2 Route: intravenous Route: single Dose: 900 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	unhealthy, 60 years (range: 33-75 years) Health Status: unhealthy Age Group: 60 years (range: 33-75 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	Disc. AE: Peripheral sensory neuropathy... AEs leading to discontinuation/dose reduction: Peripheral sensory neuropathy (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/8343268
925 mg/m2 single, intravenous Dose: 925 mg/m2 Route: intravenous Route: single Dose: 925 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	unhealthy, 60 years (range: 33-75 years) Health Status: unhealthy Age Group: 60 years (range: 33-75 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	Disc. AE: Peripheral sensory neuropathy... AEs leading to discontinuation/dose reduction: Peripheral sensory neuropathy (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/8343268
130 mg/m2 1 times / 3 weeks multiple, intravenous Dose: 130 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 130 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32670652	unhealthy, 64 years Health Status: unhealthy Age Group: 64 years Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/32670652	Disc. AE: Lhermitte's sign... AEs leading to discontinuation/dose reduction: Lhermitte's sign (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/32670652
85 mg/m2 1 times / 2 weeks multiple, intravenous Recommended Dose: 85 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 85 mg/m2, 1 times / 2 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022160s012lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022160s012lbl.pdf	Other AEs: Anaphylactic reaction... Other AEs: Anaphylactic reaction Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022160s012lbl.pdf

AEs

AE	Significance	Dose	Population
Hypersensitivity reaction	1 patient Disc. AE	130 mg/m2 single, intravenous Dose: 130 mg/m2 Route: intravenous Route: single Dose: 130 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/33131450	unhealthy, 56 years Health Status: unhealthy Age Group: 56 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/33131450
Neurotoxicity	50% DLT	135 mg/m2 1 times / 4 weeks multiple, intravenous Dose: 135 mg/m2, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 135 mg/m2, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	unhealthy, 57 years (range: 26-81 years) Health Status: unhealthy Age Group: 57 years (range: 26-81 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/2295116
Neurotoxicity	64% DLT	150 mg/m2 1 times / 4 weeks multiple, intravenous Dose: 150 mg/m2, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 150 mg/m2, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	unhealthy, 57 years (range: 26-81 years) Health Status: unhealthy Age Group: 57 years (range: 26-81 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/2295116
Neurotoxicity	71% DLT	175 mg/m2 1 times / 4 weeks multiple, intravenous Dose: 175 mg/m2, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 175 mg/m2, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	unhealthy, 57 years (range: 26-81 years) Health Status: unhealthy Age Group: 57 years (range: 26-81 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/2295116
Neurotoxicity	100% DLT	200 mg/m2 1 times / 4 weeks multiple, intravenous Dose: 200 mg/m2, 1 times / 4 weeks Route: intravenous Route: multiple Dose: 200 mg/m2, 1 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/2295116	unhealthy, 57 years (range: 26-81 years) Health Status: unhealthy Age Group: 57 years (range: 26-81 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/2295116
Thrombocytopenia	1 patient Disc. AE	55 mg/m2 multiple, intravenous Dose: 55 mg/m2 Route: intravenous Route: multiple Dose: 55 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/33012678/	unhealthy, 58 years Health Status: unhealthy Age Group: 58 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/33012678/
Diarrhoea	grade 3, 1 patient Disc. AE	150 mg/m2 1 times / 3 weeks single, intravenous Dose: 150 mg/m2, 1 times / 3 weeks Route: intravenous Route: single Dose: 150 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	unhealthy, 60 years (range: 33-75 years) Health Status: unhealthy Age Group: 60 years (range: 33-75 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/8343268
Peripheral sensory neuropathy	1 patient Disc. AE	725 mg/m2 single, intravenous Dose: 725 mg/m2 Route: intravenous Route: single Dose: 725 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	unhealthy, 60 years (range: 33-75 years) Health Status: unhealthy Age Group: 60 years (range: 33-75 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/8343268
Peripheral sensory neuropathy	1 patient Disc. AE	900 mg/m2 single, intravenous Dose: 900 mg/m2 Route: intravenous Route: single Dose: 900 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	unhealthy, 60 years (range: 33-75 years) Health Status: unhealthy Age Group: 60 years (range: 33-75 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/8343268
Peripheral sensory neuropathy	1 patient Disc. AE	925 mg/m2 single, intravenous Dose: 925 mg/m2 Route: intravenous Route: single Dose: 925 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/8343268	unhealthy, 60 years (range: 33-75 years) Health Status: unhealthy Age Group: 60 years (range: 33-75 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/8343268
Lhermitte's sign	1 patient Disc. AE	130 mg/m2 1 times / 3 weeks multiple, intravenous Dose: 130 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 130 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32670652	unhealthy, 64 years Health Status: unhealthy Age Group: 64 years Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/32670652
Anaphylactic reaction		85 mg/m2 1 times / 2 weeks multiple, intravenous Recommended Dose: 85 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 85 mg/m2, 1 times / 2 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022160s012lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022160s012lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252	inhibitor 2438	inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP 110 CYP1A2 2153 CYP2A6 879 CYP2C19 2057 CYP2E1 1060

Drug as perpetrator

Target	Modality	Activity
CYP 150	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021759s012lbl.pdf#page=29 Page: 29.0	no
CYP1A2 2333	inhibitor 4027 Sources: https://clincancerres.aacrjournals.org/content/6/4/1205.full-text.pdf	not significant
CYP2A6 911	inhibitor 4027 Sources: https://clincancerres.aacrjournals.org/content/6/4/1205.full-text.pdf	not significant
CYP2C19 2141	inhibitor 4027 Sources: https://clincancerres.aacrjournals.org/content/6/4/1205.full-text.pdf	not significant
CYP2C9 2497	inhibitor 4027 Sources: https://clincancerres.aacrjournals.org/content/6/4/1205.full-text.pdf	not significant
CYP2D6 2546	inhibitor 4027 Sources: https://clincancerres.aacrjournals.org/content/6/4/1205.full-text.pdf	not significant
CYP2E1 1146	inhibitor 4027 Sources: https://clincancerres.aacrjournals.org/content/6/4/1205.full-text.pdf	not significant
CYP3A4 2633	inhibitor 4027 Sources: https://clincancerres.aacrjournals.org/content/6/4/1205.full-text.pdf	not significant

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:31941	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:31941
ChemicalBook	CB1217931	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1217931
eMolecules	2733277	https://www.emolecules.com/cgi-bin/more?vid=2733277
eMolecules	36729906	https://www.emolecules.com/cgi-bin/more?vid=36729906
MolPort	MolPort-005-937-161	https://www.molport.com/shop/molecule-link/MolPort-005-937-161
MolPort	MolPort-006-167-572	https://www.molport.com/shop/molecule-link/MolPort-006-167-572
Selleck Chemicals	Eloxatin	http://www.selleckchem.com/products/Eloxatin.html

PubMed

Title	Date	PubMed
Recognition of platinum-DNA damage by poly(ADP-ribose) polymerase-1.	2010-07-27	20550106
Structural basis for the sequence-dependent effects of platinum-DNA adducts.	2009-05	19255091
Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates.	2005-02-15	15746072
Oxaliplatin exerts potent in vitro cytotoxicity in colorectal and pancreatic cancer cell lines and liver metastases.	2000-11-04	11062751

Patents

Sample Use Guides

In Vivo Use Guide

Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months, i.e., 12 cycles, every 2 weeks, according to the dose schedule described below for previously treated patients with advanced colorectal cancer. The recommended dose schedule given every two weeks is as follows: Day 1: ELOXATIN 85 mg/m2 IV infusion in 250-500 mL D5W and leucovorin 200 mg/m2 IV infusion in D5W both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-FU 400 mg/m2 IV bolus given over 2-4 minutes, followed by 5-FU 600 mg/m2 IV infusion in 500 mL D5W (recommended) as a 22-hour continuous infusion. Day 2: Leucovorin 200 mg/m2 IV infusion over 120 minutes, followed by 5-FU 400 mg/m2 IV bolus given over 2-4 minutes, followed by 5-FU 600 mg/m2 IV infusion in 500 mL D5W (recommended) as a 22-hour continuous infusion.

Route of Administration: Intravenous

In Vitro Use Guide

The anti-proliferative effects of oxaliplatin in human HT29 and NMG64/84 colon and COLO-357 MIA PaCa-2 and PMH2/89 pancreatic cancer cell lines and in fresh liver metastases from patients with colorectal and pancreatic cancer were investigated using the human tumor colony forming assay. Oxaliplatin significantly inhibited the colony formation in all cell lines in a concentration- and time-dependent manner. All liver tumors displayed a significant concentration-dependent inhibition of colony formation after exposure to oxaliplatin for 2 hours. The IC50 of oxaliplatin of 9 of the 10 tumors was < 10 micrograms/ml.

Name

Type

Language

NSC-194814

Preferred Name

English

DICHLORO-1,2-DIAMINOCYCLOHEXANE PLATINUM COMPLEX

Common Name

English

cis-Dichloro(1,2-diaminecyclohexane)platinum(II)

Systematic Name

English

(SP-4-2)-Dichloro(1,2-cyclohexanediamine-?N1,?N2)platinum

Systematic Name

English

Code System Code Type Description

FDA UNII

46C5C7KWD3