COBIMETINIB FUMARATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	2C21H21F3IN3O2.C4H4O4
Molecular Weight	1178.6922
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C\C(O)=O.[H][C@]1(CCCCN1)C2(O)CN(C2)C(=O)C3=C(NC4=CC=C(I)C=C4F)C(F)=C(F)C=C3.[H][C@]5(CCCCN5)C6(O)CN(C6)C(=O)C7=C(NC8=CC=C(I)C=C8F)C(F)=C(F)C=C7

InChI

InChIKey=RESIMIUSNACMNW-BXRWSSRYSA-N

InChI=1S/2C21H21F3IN3O2.C4H4O4/c2*22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17;5-3(6)1-2-4(7)8/h2*4-7,9,17,26-27,30H,1-3,8,10-11H2;1-2H,(H,5,6)(H,7,8)/b;;2-1+/t2*17-;/m00./s1

HIDE SMILES / InChI

Molecular Formula	C21H21F3IN3O2
Molecular Weight	531.31
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	C4H4O4
Molecular Weight	116.0722
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf
Curator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB05239 http://www.exelixis.com/pipeline/GDC_0973_xl518

Cobimetinib is an orally active, potent and highly selective small molecule inhibiting mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), and central components of the RAS/RAF/MEK/ERK signal transduction pathway. It has been approved in Switzerland and the US, in combination with vemurafenib for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma. Preclinical studies have demonstrated that Cobimetinib is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signalling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors becomes BRAF-inhibitor resistant due to reactivation of MAPK signalling. BRAF-inhibitor resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK. Cobimetinib specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Cobimetinib is used for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Cobimetinib is used in combination with vemurafenib, a BRAF inhibitor. Cobimetinib is marketed under the trade name Cotellic.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dual specificity mitogen-activated protein kinase kinase 1 20 Target ID: CHEMBL3587 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf https://www.ncbi.nlm.nih.gov/pubmed/22084396	Inhibitor 8297		4.2 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf	Primary		Approved 8429	COTELLIC Approved Use COTELLIC is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. Launch Date 2015

C_max

Value	Dose	Co-administered	Analyte	Population
273 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206192s002lbl.pdf	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		COBIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
4340 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206192s002lbl.pdf	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	COBIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
268 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02300025	10 mg single, oral dose: 10 mg route of administration: oral experiment type: single co-administered:	COBIMETINIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status: Fasted
498 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02300025	10 mg single, oral dose: 10 mg route of administration: oral experiment type: single co-administered:	COBIMETINIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status: Fasted
539 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02300025	10 mg single, oral dose: 10 mg route of administration: oral experiment type: single co-administered:	COBIMETINIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status: Fasted

T_1/2

Value	Dose	Analyte	Population
44 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206192s002lbl.pdf	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	COBIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
143 h Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02300025	10 mg single, oral dose: 10 mg route of administration: oral experiment type: single co-administered:	COBIMETINIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status: Fasted
95.2 h Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02300025	10 mg single, oral dose: 10 mg route of administration: oral experiment type: single co-administered:	COBIMETINIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status: Fasted
104 h Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02300025	10 mg single, oral dose: 10 mg route of administration: oral experiment type: single co-administered:	COBIMETINIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status: Fasted

F_unbound

Value	Dose	Co-administered	Analyte	Population
5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206192s002lbl.pdf	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		COBIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
60 mg 1 times / day steady, oral Recommended Dose: 60 mg, 1 times / day Route: oral Route: steady Dose: 60 mg, 1 times / day Co-administed with:: vemurafenib(960 mg twice daily on Days 1 -28) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf	unhealthy, 55 years (range: 23 - 88 years) n = 185 Health Status: unhealthy Condition: BRAF V600 mutation-positive, unresectable or metastatic melanoma Age Group: 55 years (range: 23 - 88 years) Sex: M+F Population Size: 185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf	Other AEs: Lymphopenia, Lymphopenia... Other AEs: Lymphopenia (grade 1-2, 63%) Lymphopenia (grade 3-4, 10%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf
60 mg 1 times / day steady, oral Recommended Dose: 60 mg, 1 times / day Route: oral Route: steady Dose: 60 mg, 1 times / day Co-administed with:: vemurafenib(960 mg twice daily on Days 1 -28) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf	unhealthy, 55 years (range: 23 - 88 years) n = 213 Health Status: unhealthy Condition: BRAF V600 mutation-positive, unresectable or metastatic melanoma Age Group: 55 years (range: 23 - 88 years) Sex: M+F Population Size: 213 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf	Other AEs: Creatine phosphokinase increased, Creatine phosphokinase increased... Other AEs: Creatine phosphokinase increased (grade 1-2, 65%) Creatine phosphokinase increased (grade 3-4, 14%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf
60 mg 1 times / day steady, oral Recommended Dose: 60 mg, 1 times / day Route: oral Route: steady Dose: 60 mg, 1 times / day Co-administed with:: vemurafenib(960 mg twice daily on Days 1 -28) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf	unhealthy, 55 years (range: 23 - 88 years) n = 247 Health Status: unhealthy Condition: BRAF V600 mutation-positive, unresectable or metastatic melanoma Age Group: 55 years (range: 23 - 88 years) Sex: M+F Population Size: 247 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf	Disc. AE: Aspartate aminotransferase increased, Gamma-glutamyltransferase increased... Other AEs: Rash, Diarrhea... AEs leading to discontinuation/dose reduction: Aspartate aminotransferase increased (2.4%) Gamma-glutamyltransferase increased (1.6%) Alanine aminotransferase increased (1.6%) Rash (1.6%) Pyrexia (1.2%) Retinal detachment (2%) Other AEs: Rash (11%) Diarrhea (9%) Chorioretinopathy (7%) Pyrexia (6%) Vomiting (6%) Nausea (5%) Creatine phosphokinase increased (4.9%) Diarrhea (grade 1-2, 54%) Diarrhea (grade 3-4, 6%) Nausea (grade 1-2, 40%) Nausea (grade 3-4, 1%) Vomiting (grade 1-2, 23%) Vomiting (grade 3-4, 1%) Stomatitis (grade 1-2, 13%) Aphthous stomatitis (grade 1-2, 13%) Mouth ulceration (grade 1-2, 13%) Mucosal inflammation (grade 1-2, 13%) Stomatitis (grade 3-4, 1%) Aphthous stomatitis (grade 3-4, 1%) Mouth ulceration (grade 3-4, 1%) Mucosal inflammation (grade 3-4, 1%) Solar dermatitis (grade 1-2, 42%) Sunburn (grade 1-2, 42%) Photosensitivity reaction (grade 1-2, 42%) Solar dermatitis (grade 3-4, 4%) Sunburn (grade 3-4, 4%) Photosensitivity reaction (grade 3-4, 4%) Acneiform dermatitis (grade 1-2, 14%) Acneiform dermatitis (grade 3-4, 2%) Pyrexia (grade 1-2, 26%) Pyrexia (grade 3-4, 2%) Chills (grade 1-2, 10%) Hypertension (grade 1-2, 11%) Hypertension (grade 3-4, 4%) Hemorrhage (grade 1-2, 12%) Rectal hemorrhage (grade 1-2, 12%) Melena (grade 1-2, 12%) Hemorrhoidal hemorrhage (grade 1-2, 12%) Gastrointestinal hemorrhage (grade 1-2, 12%) Hematemesis (grade 1-2, 12%) Hematochezia (grade 1-2, 12%) Gingival bleeding (grade 1-2, 12%) Metrorrhagia (grade 1-2, 12%) Uterine hemorrhage (grade 1-2, 12%) Hemorrhagic ovarian cyst (grade 1-2, 12%) Menometrorrhagia (grade 1-2, 12%) Menorrhagia (grade 1-2, 12%) Vaginal hemorrhage (grade 1-2, 12%) Hemoptysis (grade 1-2, 12%) Cerebral hemorrhage (grade 1-2, 12%) Subarachnoid hemorrhage (grade 1-2, 12%) Subgaleal hematoma (grade 1-2, 12%) Hematuria (grade 1-2, 12%) Epistaxis (grade 1-2, 12%) Contusion (grade 1-2, 12%) Traumatic hematoma (grade 1-2, 12%) Ecchymosis (grade 1-2, 12%) Purpura (grade 1-2, 12%) Nail bed bleeding (grade 1-2, 12%) Ocular hemorrhage (grade 1-2, 12%) Eye hemorrhage (grade 1-2, 12%) Conjunctival hemorrhage (grade 1-2, 12%) Retinal hemorrhage (grade 1-2, 12%) Hemorrhage (grade 3-4, 1%) Rectal hemorrhage (grade 3-4, 1%) Melena (grade 3-4, 1%) Hemorrhoidal hemorrhage (grade 3-4, 1%) Gastrointestinal hemorrhage (grade 3-4, 1%) Hematemesis (grade 3-4, 1%) Hematochezia (grade 3-4, 1%) Gingival bleeding (grade 3-4, 1%) Metrorrhagia (grade 3-4, 1%) Uterine hemorrhage (grade 3-4, 1%) Hemorrhagic ovarian cyst (grade 3-4, 1%) Menometrorrhagia (grade 3-4, 1%) Menorrhagia (grade 3-4, 1%) Vaginal hemorrhage (grade 3-4, 1%) Hemoptysis (grade 3-4, 1%) Cerebral hemorrhage (grade 3-4, 1%) Subarachnoid hemorrhage (grade 3-4, 1%) Subgaleal hematoma (grade 3-4, 1%) Hematuria (grade 3-4, 1%) Epistaxis (grade 3-4, 1%) Contusion (grade 3-4, 1%) Traumatic hematoma (grade 3-4, 1%) Ecchymosis (grade 3-4, 1%) Purpura (grade 3-4, 1%) Nail bed bleeding (grade 3-4, 1%) Ocular hemorrhage (grade 3-4, 1%) Eye hemorrhage (grade 3-4, 1%) Conjunctival hemorrhage (grade 3-4, 1%) Retinal hemorrhage (grade 3-4, 1%) Vision blurred (grade 1-2, 14%) Visual acuity reduced (grade 1-2, 14%) Visual impairment (grade 1-2, 14%) Vision blurred (grade 3-4, <1%) Visual acuity reduced (grade 3-4, <1%) Visual impairment (grade 3-4, <1%) Chorioretinopathy (grade 1-2, 13%) Chorioretinopathy (grade 3-4, <1%) Retinal detachment (grade 1-2, 10%) Detachment of retinal pigment epithelium (grade 1-2, 10%) Detachment of macular retinal pigment epithelium (grade 1-2, 10%) Retinal detachment (grade 3-4, 2%) Detachment of retinal pigment epithelium (grade 3-4, 2%) Detachment of macular retinal pigment epithelium (grade 3-4, 2%) Alopecia (15%) Hyperkeratosis (11%) Erythema (10%) Creatinine increased (grade 1-2, 96.3%) Creatinine increased (grade 3-4, 3.3%) AST increased (grade 1-2, 65%) AST increased (grade 3-4, 8%) ALT increased (grade 1-2, 57%) ALT increased (grade 3-4, 11%) Alkaline phosphatase increased (grade 1-2, 64%) Alkaline phosphatase increased (grade 3-4, 7%) Hypophosphatemia (grade 1-2, 56%) Hypophosphatemia (grade 3-4, 12%) GGT increased (grade 1-2, 44%) GGT increased (grade 3-4, 21%) Hyponatremia (grade 1-2, 32%) Hyponatremia (grade 3-4, 6%) Hypoalbuminemia (grade 1-2, 41.2%) Hypoalbuminemia (grade 3-4, 0.8%) Hypokalemia (grade 1-2, 20.5%) Hypokalemia (grade 3-4, 4.5%) Hyperkalemia (grade 1-2, 23.1%) Hyperkalemia (grade 3-4, 2.9%) Hypocalcemia (grade 1-2, 23.6%) Hypocalcemia (grade 3-4, 0.4%) Anemia (grade 1-2, 66.5%) Anemia (grade 3-4, 2.5%) Thrombocytopenia (grade 1-2, 18%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf
125 mg 1 times / day steady, oral Highest studied dose Dose: 125 mg, 1 times / day Route: oral Route: steady Dose: 125 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27424159	unhealthy, 60 years (range: 30−82 years) Health Status: unhealthy Condition: metastatic or unresectable solid tumors Age Group: 60 years (range: 30−82 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/27424159	DLT: Rash, Central serous retinopathy... Dose limiting toxicities: Rash (grade 3) Central serous retinopathy (grade 3, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/27424159
80 mg 1 times / day steady, oral Highest studied dose Dose: 80 mg, 1 times / day Route: oral Route: steady Dose: 80 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27424159	unhealthy, 60 years (range: 30−82 years) n = 27 Health Status: unhealthy Condition: metastatic or unresectable solid tumors Age Group: 60 years (range: 30−82 years) Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/27424159	DLT: Diarrhea, Rash... Dose limiting toxicities: Diarrhea (grade 3, 1 patient) Rash (grade 3, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/27424159
100 mg 1 times / day steady, oral MTD Dose: 100 mg, 1 times / day Route: oral Route: steady Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27424159	unhealthy, 60 years (range: 30−82 years) n = 29 Health Status: unhealthy Condition: metastatic or unresectable solid tumors Age Group: 60 years (range: 30−82 years) Sex: M+F Population Size: 29 Sources: https://pubmed.ncbi.nlm.nih.gov/27424159	Other AEs: Diarrhea, Diarrhea... Other AEs: Diarrhea (all grades, 79%) Diarrhea (grade 3-5, 14%) Rash (all grades, 66%) Dermatitis acneiform (all grades, 66%) Rash pruritic (all grades, 66%) Generalized rash (all grades, 66%) Dermatitis (all grades, 66%) Exfoliative rash (all grades, 66%) Rash erythematous (all grades, 66%) Rash maculo-papular (all grades, 66%) Rash (grade 3-5, 10%) Dermatitis acneiform (grade 3-5, 10%) Rash pruritic (grade 3-5, 10%) Generalized rash (grade 3-5, 10%) Dermatitis (grade 3-5, 10%) Exfoliative rash (grade 3-5, 10%) Rash erythematous (grade 3-5, 10%) Rash maculo-papular (grade 3-5, 10%) Fatigue (all grades, 66%) Fatigue (grade 3-5, 7%) Peripheral edema (all grades, 34%) Periorbital edema (all grades, 34%) Edema (all grades, 34%) Edema face (all grades, 34%) Nausea (all grades, 41%) Vomiting (all grades, 48%) Abnormal sensation in eye (all grades, 24%) Retinal edema (all grades, 24%) Photopsia (all grades, 24%) Blurred vision (all grades, 24%) Central serous retinopathy (all grades, 24%) Vitreous floaters (all grades, 24%) Eye disorder NOS (all grades, 24%) Abnormal sensation in eye (grade 3-5, 3%) Retinal edema (grade 3-5, 3%) Photopsia (grade 3-5, 3%) Blurred vision (grade 3-5, 3%) Central serous retinopathy (grade 3-5, 3%) Vitreous floaters (grade 3-5, 3%) Eye disorder NOS (grade 3-5, 3%) Abdominal pain upper (all grades, 35%) Abdominal pain lower (all grades, 35%) Abdominal discomfort (all grades, 35%) Abdominal tenderness (all grades, 35%) Abdominal pain upper (grade 3-5, 3%) Abdominal pain lower (grade 3-5, 3%) Abdominal discomfort (grade 3-5, 3%) Abdominal tenderness (grade 3-5, 3%) Stomatitis (all grades, 10%) Dry skin (all grades, 10%) Sources: https://pubmed.ncbi.nlm.nih.gov/27424159
60 mg 1 times / day steady, oral MTD Dose: 60 mg, 1 times / day Route: oral Route: steady Dose: 60 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27424159 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000MedR.pdf	unhealthy, 60 years (range: 30−82 years) n = 27 Health Status: unhealthy Condition: metastatic or unresectable solid tumors Age Group: 60 years (range: 30−82 years) Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/27424159 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000MedR.pdf	DLT: Rash, Dermatitis acneiform... Other AEs: Diarrhea, Rash... Dose limiting toxicities: Rash (grade 3-5, 4%) Dermatitis acneiform (grade 3-5, 4%) Rash pruritic (grade 3-5, 4%) Generalized rash (grade 3-5, 4%) Dermatitis (grade 3-5, 4%) Exfoliative rash (grade 3-5, 4%) Rash erythematous (grade 3-5, 4%) Rash maculo-papular (grade 3-5, 4%) Other AEs: Diarrhea (all grades, 56%) Rash (all grades, 67%) Dermatitis acneiform (all grades, 67%) Rash pruritic (all grades, 67%) Generalized rash (all grades, 67%) Dermatitis (all grades, 67%) Exfoliative rash (all grades, 67%) Rash erythematous (all grades, 67%) Rash maculo-papular (all grades, 67%) Fatigue (all grades, 33%) Fatigue (grade 3-5, 11%) Peripheral edema (all grades, 33%) Periorbital edema (all grades, 33%) Edema (all grades, 33%) Edema face (all grades, 33%) Nausea (all grades, 22%) Vomiting (all grades, 11%) Abnormal sensation in eye (all grades, 15%) Retinal edema (all grades, 15%) Photopsia (all grades, 15%) Blurred vision (all grades, 15%) Central serous retinopathy (all grades, 15%) Vitreous floaters (all grades, 15%) Eye disorder NOS (all grades, 15%) Stomatitis (all grades, 11%) Dry skin (all grades, 7%) Sources: https://pubmed.ncbi.nlm.nih.gov/27424159 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000MedR.pdf
40 mg 1 times / day steady, oral Dose: 40 mg, 1 times / day Route: oral Route: steady Dose: 40 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27424159	unhealthy, 60 years (range: 30−82 years) n = 27 Health Status: unhealthy Condition: metastatic or unresectable solid tumors Age Group: 60 years (range: 30−82 years) Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/27424159	DLT: Encephalopathy... Dose limiting toxicities: Encephalopathy (grade 4, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/27424159

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	substrate 1037 inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478 P-gp 1461 BCRP 699 OATP1B1 788 OATP1B3 706 OCT1 512	CYP1A2 1054 CYP2A6 543 CYP2B6 664 CYP2C19 991 CYP2C8 693 UGT2B7 389 UGT1A1 418 UGT1A3 422 UGT1A4 347 UGT1A6 307 UGT1A7 236 UGT1A9 380 UGT1A10 291 UGT2B4 249 UGT2B15 203 UGT2B17 213 P-gp 1537 BCRP 561 OATP1B1 406 OATP1B3 350 OCT1 327	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	no [IC50 118 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=39 Page: 39.0	no [IC50 40 uM]
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	no [IC50 85 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no [IC50 >50 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no [IC50 >50 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no [IC50 >50 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no [IC50 >50 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no [IC50 >50 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=39 Page: 39.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	yes [IC50 1.8 uM]	no (co-administration study) Comment: Coadministration of cobimetinib 60 mg QD for 15 days with a single dose of dextromethorphan 2 mg did not change dextromethorphan exposure Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	yes [IC50 17 uM]	no (co-administration study) Comment: Coadministration of cobimetinib 60 mg QD for 15 days with a single dose of midazolam 2 mg did not change midazolam exposure Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	major	yes (co-administration study) Comment: Coadministration of itraconazole 200 mg QD for 14 days with a single dose of 10 mg cobimetinib increased cobimetinib AUC by 6.7-fold (90% CI: 5.6, 8.0) and Cmax by 3.2-fold (90% CI: 2.7, 3.7) as compared with cobimetinib alone Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	minor
CYP2A6 543	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	minor
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	minor
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	minor
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	minor
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	minor
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	minor
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT1A1 418	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT1A10 291	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT1A3 422	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT1A4 347	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT1A6 307	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT1A7 236	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT1A9 380	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT2B15 203	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT2B17 213	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
UGT2B4 249	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	yes
UGT2B7 389	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000PharmR.pdf#page=14 Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90851	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90851
ChemicalBook	CB32551361	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32551361
MolPort	MolPort-028-720-358	https://www.molport.com/shop/molecule-link/MolPort-028-720-358
ZINC	ZINC000060325170	http://zinc15.docking.org/substances/ZINC000060325170

PubMed

Title	Date	PubMed
MEK and the inhibitors: from bench to bedside.	2013 Apr 12	23587417
Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors.	2015 Nov	26365290
Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells.	2015 Sep 18	26384788
MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy.	2016	26730180
Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans.	2016 Jan	26451002

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose is 60 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

Route of Administration: Oral

In Vitro Use Guide

Cobimetinib was shown to potently inhibit the phosphorylation of ERK and MCL-1, and to attenuate MCL-1 expression in a dose-dependent manner (2.5-10 uM) in RKO cells

Substance Class	Chemical Created by `admin` on `Fri Dec 15 20:19:33 GMT 2023` Edited by `admin` on `Fri Dec 15 20:19:33 GMT 2023`
Record UNII	6EXI96H8SV
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

COBIMETINIB FUMARATE

Official Name

English

COTELLIC

Brand Name

English

XL-518 HEMIFUMARATE

Common Name

English

COBIMETINIB HEMIFUMARATE

Common Name

English

Bis({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}{3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}methanone) (2E)-but-2-enedioate

Common Name

English

COBIMETINIB FUMARATE [MI]

Common Name

English

COBIMETINIB FUMARATE [JAN]

Common Name

English

Cobimetinib hemifumarate [WHO-DD]

Common Name

English

COBIMETINIB FUMARATE [ORANGE BOOK]

Common Name

English

COBIMETINIB FUMARATE [USAN]

Common Name

English

METHANONE, (3,4-DIFLUORO-2-((2-FLUORO-4-IODOPHENYL)AMINO)PHENYL)(3-HYDROXY-3-(2S)-2-PIPERIDINYL-1-AZETIDINYL)-, (2E)-2-BUTENEDIOATE (2:1)

Common Name

English

GDC-0973 HEMIFUMARATE

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

COTELLIC (AUTHORIZED: MELANOMA)