IXAZOMIB CITRATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H23BCl2N2O9
Molecular Weight	517.122
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)C[C@H](NC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)B2OC(=O)C(CC(O)=O)(CC(O)=O)O2

InChI

InChIKey=MBOMYENWWXQSNW-AWEZNQCLSA-N

InChI=1S/C20H23BCl2N2O9/c1-10(2)5-14(21-33-19(32)20(34-21,7-16(27)28)8-17(29)30)25-15(26)9-24-18(31)12-6-11(22)3-4-13(12)23/h3-4,6,10,14H,5,7-9H2,1-2H3,(H,24,31)(H,25,26)(H,27,28)(H,29,30)/t14-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C20H23BCl2N2O9
Molecular Weight	517.122
Charge	0
Count

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

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208462s001lbl.pdf | http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003844/WC500217620.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf
Curator's Comment: description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT02630030 | https://www.ncbi.nlm.nih.gov/pubmed/24486586 | https://www.ncbi.nlm.nih.gov/pubmed/25016815 | https://www.ncbi.nlm.nih.gov/pubmed/25605842

Ixazomib (trade name Ninlaro) is a drug for the treatment of multiple myeloma in adults after at least one prior therapy, in combination with lenalidomide and dexamethasone. It is taken by mouth in form of capsules. Common side effects include diarrhea, constipation and low platelet count. Like the older bortezomib (which can only be given by injection), it acts as a proteasome inhibitor, has orphan drug status in the US and Europe. At therapeutic concentrations, ixazomib selectively and reversibly inhibits the protein proteasome subunit beta type-5 (PSMB5) with a dissociation half-life of 18 minutes. This mechanism is the same as of bortezomib, which has a much longer dissociation half-life of 110 minutes; the related drug carfilzomib, by contrast, blocks PSMB5 irreversibly. Proteasome subunits beta type-1 and type-2 are only inhibited at high concentrations reached in cell culture models. PSMB5 is part of the 20S proteasome complex and has enzymatic activity similar to chymotrypsin. It induces apoptosis, a type of programmed cell death, in various cancer cell lines. A synergistic effect of ixazomib and lenalidomide has been found in a large number of myeloma cell lines. The medication is taken orally as a prodrug, ixazomib citrate, which is a boronic ester; this ester rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib, a boronic acid. Absolute bioavailability is 58%, and highest blood plasma concentrations of ixazomib are reached after one hour. Plasma protein binding is 99%.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Proteasome subunit beta type-5 6 Target ID: P28074\|\|\|Q86T01 Gene ID: 5693.0 Gene Symbol: PSMB5 Target Organism: Homo sapiens (Human) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208462s001lbl.pdf	Inhibitor 8297	0.93 nM [Ki]
Proteasome subunit beta type-5 6 Target ID: P28074\|\|\|Q86T01 Gene ID: 5693.0 Gene Symbol: PSMB5 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/25605842	Inhibitor 8297	3.4 nM [IC50]
Proteasome subunit beta type-2 3 Target ID: P49721 Gene ID: 5690.0 Gene Symbol: PSMB2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/25605842	Inhibitor 8297	3500.0 nM [IC50]
Proteasome subunit beta type-1 3 Target ID: P20618 Gene ID: 5689.0 Gene Symbol: PSMB1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/25605842	Inhibitor 8297	31.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Multiple myeloma 159 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208462s001lbl.pdf	Primary	Approved 8429	NINLARO Approved Use NINLARO is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Launch Date 2015
Multiple myeloma 159 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf	Primary	Approved 8429	NINLARO Approved Use INDICATIONS AND USAGE. NINLARO is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Launch Date 2015
Glioblastoma 65 Sources: https://clinicaltrials.gov/ct2/show/NCT02630030	Primary	Phase I 428	NINLARO Approved Use INDICATIONS AND USAGE. NINLARO is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Launch Date 2015
Bladder cancer 16 Sources: https://clinicaltrials.gov/ct2/show/NCT02420847	Primary	Phase II 1132	NINLARO Approved Use INDICATIONS AND USAGE. NINLARO is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Launch Date 2015

C_max

Value	Dose	Analyte	Population
77 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26872892	4 mg single, oral dose: 4 mg route of administration: Oral experiment type: SINGLE co-administered:	IXAZOMIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
22.8 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26872892	4 mg single, oral dose: 4 mg route of administration: Oral experiment type: SINGLE co-administered:	IXAZOMIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
77 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26872892/	4 mg 3 times / 2 weeks multiple, oral dose: 4 mg route of administration: Oral experiment type: MULTIPLE co-administered:	IXAZOMIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
25.8 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27196567/	3 mg single, oral dose: 3 mg route of administration: Oral experiment type: SINGLE co-administered:	IXAZOMIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
22.8 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26872892/	4 mg 3 times / 2 weeks multiple, oral dose: 4 mg route of administration: Oral experiment type: MULTIPLE co-administered:	IXAZOMIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT

AUC

Value	Dose	Analyte	Population
1470 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26872892	4 mg single, oral dose: 4 mg route of administration: Oral experiment type: SINGLE co-administered:	IXAZOMIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
999 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26872892	4 mg single, oral dose: 4 mg route of administration: Oral experiment type: SINGLE co-administered:	IXAZOMIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
1470 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26872892/	4 mg 3 times / 2 weeks multiple, oral dose: 4 mg route of administration: Oral experiment type: MULTIPLE co-administered:	IXAZOMIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
575 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27196567/	3 mg single, oral dose: 3 mg route of administration: Oral experiment type: SINGLE co-administered:	IXAZOMIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
999 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26872892/	4 mg 3 times / 2 weeks multiple, oral dose: 4 mg route of administration: Oral experiment type: MULTIPLE co-administered:	IXAZOMIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
1161.92 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1.33 mg/m^2 1 times / 3 days multiple, intravenous dose: 1.33 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
1542.63999999999 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1.76 mg/m^2 1 times / 3 days multiple, intravenous dose: 1.76 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
191.87 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1 mg/m^2 single, intravenous dose: 1 mg/m^2 route of administration: intravenous experiment type: single co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
301 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	0.5 mg/m^2 1 times / 3 days multiple, intravenous dose: 0.5 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
3800 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	2.34 mg/m^2 1 times / 3 days multiple, intravenous dose: 2.34 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
391.46 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1.33 mg/m^2 single, intravenous dose: 1.33 mg/m^2 route of administration: intravenous experiment type: single co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
522.74 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1.76 mg/m^2 single, intravenous dose: 1.76 mg/m^2 route of administration: intravenous experiment type: single co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
579.91 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1 mg/m^2 1 times / 3 days multiple, intravenous dose: 1 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
60.9 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	0.25 mg/m^2 1 times / 3 days multiple, intravenous dose: 0.25 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
620 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	2.34 mg/m^2 single, intravenous dose: 2.34 mg/m^2 route of administration: intravenous experiment type: single co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
91.6 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	0.5 mg/m^2 single, intravenous dose: 0.5 mg/m^2 route of administration: intravenous experiment type: single co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:

T_1/2

Value	Dose	Analyte	Population
144.69 h Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1.33 mg/m^2 1 times / 3 days multiple, intravenous dose: 1.33 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
104.84 h Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1.76 mg/m^2 1 times / 3 days multiple, intravenous dose: 1.76 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
90.8 h Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	2.34 mg/m^2 1 times / 3 days multiple, intravenous dose: 2.34 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
171.9 h Clinical Trial https://clinicaltrials.gov/ct2/show/NCT00830869	1 mg/m^2 1 times / 3 days multiple, intravenous dose: 1 mg/m^2 route of administration: intravenous experiment type: multiple co-administered:	IXAZOMIB plasma	Homo sapiens population: unhealthy age: Adults sex: food status:
9.5 day EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28290121/	multiple, oral	IXAZOMIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27196567/	3 mg single, oral dose: 3 mg route of administration: Oral experiment type: SINGLE co-administered:		IXAZOMIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf			IXAZOMIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1.76 mg/m2 3 times / month multiple, intravenous Dose: 1.76 mg/m2, 3 times / month Route: intravenous Route: multiple Dose: 1.76 mg/m2, 3 times / month Sources: https://pubmed.ncbi.nlm.nih.gov/25325301	unhealthy, 45 years (range: 23–73 years) n = 7 Health Status: unhealthy Condition: non-hematologic malignancies Age Group: 45 years (range: 23–73 years) Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/25325301	DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 4, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/25325301
3.11 mg/m2 3 times / month multiple, intravenous Highest studied dose Dose: 3.11 mg/m2, 3 times / month Route: intravenous Route: multiple Dose: 3.11 mg/m2, 3 times / month Sources: https://pubmed.ncbi.nlm.nih.gov/25325301	unhealthy, 56 years (range: 27–72 years) n = 5 Health Status: unhealthy Condition: non-hematologic malignancies Age Group: 56 years (range: 27–72 years) Sex: M+F Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/25325301	DLT: Acute renal failure, Diarrhea... Dose limiting toxicities: Acute renal failure (grade 3, 1 patient) Diarrhea (grade 2-3, 2 patients) Vomiting (grade 2-3, 2 patients) Fatigue (grade 2, 1 patient) Nausea (grade 2, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/25325301
5.5 mg 3 times / month multiple, oral Highest studied dose Dose: 5.5 mg, 3 times / month Route: oral Route: multiple Dose: 5.5 mg, 3 times / month Sources: https://pubmed.ncbi.nlm.nih.gov/28550039	unhealthy, 66.0 years (range: 54–77 years) n = 5 Health Status: unhealthy Condition: relapsed or refractory light-chain (AL) amyloidosis Age Group: 66.0 years (range: 54–77 years) Sex: M+F Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/28550039	DLT: Diarrhea, Renal failure... Dose limiting toxicities: Diarrhea (grade 3, 1 patient) Renal failure (grade 2, 1 patient) Failure respiratory (grade 2, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/28550039
4 mg 3 times / month multiple, oral MTD\|RP2D\|Recommended Dose: 4 mg, 3 times / month Route: oral Route: multiple Dose: 4 mg, 3 times / month Sources: https://pubmed.ncbi.nlm.nih.gov/28550039	unhealthy, 66.0 years (range: 54–77 years) n = 6 Health Status: unhealthy Condition: relapsed or refractory light-chain (AL) amyloidosis Age Group: 66.0 years (range: 54–77 years) Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/28550039	DLT: Thrombocytopenia... Dose limiting toxicities: Thrombocytopenia (grade 3, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/28550039
2.34 mg/m2 3 times / month multiple, intravenous MTD Dose: 2.34 mg/m2, 3 times / month Route: intravenous Route: multiple Dose: 2.34 mg/m2, 3 times / month Sources: https://pubmed.ncbi.nlm.nih.gov/25325301	unhealthy, 69.5 years (range: 47–75 years) n = 10 Health Status: unhealthy Condition: non-hematologic malignancies Age Group: 69.5 years (range: 47–75 years) Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/25325301	DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 3, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/25325301
3.95 mg/m2 1 times / week multiple, oral Highest studied dose Dose: 3.95 mg/m2, 1 times / week Route: oral Route: multiple Dose: 3.95 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24904120	unhealthy, 64.0 years (range: 40-76 years) n = 4 Health Status: unhealthy Condition: relapsed/refractory multiple myeloma Age Group: 64.0 years (range: 40-76 years) Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/24904120	DLT: Nausea, Vomiting... Dose limiting toxicities: Nausea (grade 3, 1 patient) Vomiting (grade 3, 1 patient) Diarrhea (grade 3, 1 patient) Erythema multiforme (grade 3, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/24904120
2.97 mg/m2 1 times / week multiple, oral MTD Dose: 2.97 mg/m2, 1 times / week Route: oral Route: multiple Dose: 2.97 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24904120	unhealthy, 64.0 years (range: 40-76 years) Health Status: unhealthy Condition: relapsed/refractory multiple myeloma Age Group: 64.0 years (range: 40-76 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/24904120	DLT: Nausea, Vomiting... Dose limiting toxicities: Nausea (grade 3, 1 patient) Vomiting (grade 3, 1 patient) Diarrhea (grade 3, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/24904120
4 mg 1 times / week multiple, oral Recommended Dose: 4 mg, 1 times / week Route: oral Route: multiple Dose: 4 mg, 1 times / week Co-administed with:: lenalidomide(25 mg on Days 1 throughn21) dexamethasone(40 mg on Days 1, 8, 15, and 22 of a 28-day cycle) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf	unhealthy, 66 years (range: 38 - 91 years) n = 360 Health Status: unhealthy Condition: relapsed and/or refractory multiple myeloma Age Group: 66 years (range: 38 - 91 years) Sex: M+F Population Size: 360 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf	Other AEs: Upper respiratory tract infection, Upper respiratory tract infection... Other AEs: Upper respiratory tract infection (grade 1-2, 19%) Upper respiratory tract infection (grade 3, <1%) Peripheral neuropathies (grade 1-2, 28%) Peripheral neuropathies (grade 3, 2%) Diarrhea (grade 1-2, 42%) Diarrhea (grade 3, 6%) Constipation (grade 1-2, 34%) Constipation (grade 3, <1%) Nausea (grade 1-2, 26%) Nausea (grade 3, 2%) Vomiting (grade 1-2, 22%) Vomiting (grade 3, 1%) Rash (grade 1-2, 19%) Rash (grade 3, 3%) Back pain (grade 1-2, 21%) Back pain (grade 3, <1%) Edema peripheral (grade 1-2, 25%) Edema peripheral (grade 3, 2%) Thrombocytopenia (grade 1-2, 78%) Thrombocytopenia (grade 3, 26%) Neutropenia (grade 1-2, 67%) Neutropenia (grade 3, 26%) Blurred vision (all grades, 3%) Dry eye (5%) Conjunctivitis (6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf
4 mg 1 times / week multiple, oral MTD Dose: 4 mg, 1 times / week Route: oral Route: multiple Dose: 4 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/28550039	unhealthy, 66.0 years (range: 54–77 years) n = 6 Health Status: unhealthy Condition: relapsed/refractory AL amyloidosis Age Group: 66.0 years (range: 54–77 years) Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/28550039	DLT: Thrombocytopenia... Dose limiting toxicities: Thrombocytopenia (grade 3, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/28550039
5.5 mg 1 times / week multiple, oral Dose: 5.5 mg, 1 times / week Route: oral Route: multiple Dose: 5.5 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/28550039	unhealthy, 66.0 years (range: 54–77 years) n = 5 Health Status: unhealthy Condition: relapsed/refractory AL amyloidosis Age Group: 66.0 years (range: 54–77 years) Sex: M+F Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/28550039	DLT: Diarrhea, Renal failure... Dose limiting toxicities: Diarrhea (grade 3, 1 patient) Renal failure (grade 2, 1 patient) Dyspnea (grade 2, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/28550039
2.97 mg/m2 1 times / week multiple, oral Recommended Dose: 2.97 mg/m2, 1 times / week Route: oral Route: multiple Dose: 2.97 mg/m2, 1 times / week Co-administed with:: lenalidomide(25mg, PO, 1-21 day) dexamethasone(40mg, PO, 1-21 day, Days 1, 8, 15, 22) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf Page: C16005	unhealthy, adult n = 31 Health Status: unhealthy Condition: cancer Age Group: adult Sex: M+F Population Size: 31 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf Page: C16005	Disc. AE: Thrombocytopenia, Diarrhea... Other AEs: Renal failure... AEs leading to discontinuation/dose reduction: Thrombocytopenia (1 patient) Diarrhea (1 patient) Nausea and vomiting (1 patient) Hypercalcemia (1 patient) Dyspnea (1 patient) Other AEs: Renal failure (2 patients) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf Page: C16005
4 mg 1 times / week multiple, oral Recommended Dose: 4 mg, 1 times / week Route: oral Route: multiple Dose: 4 mg, 1 times / week Co-administed with:: lenalidomide(25 mg on Days 1 throughn21) dexamethasone(40 mg on Days 1, 8, 15, and 22 of a 28-day cycle) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000MedR.pdf Page: p. 55	unhealthy n = 360 Health Status: unhealthy Population Size: 360 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000MedR.pdf Page: p. 55	Disc. AE: Diarrhea, Fatigue... AEs leading to discontinuation/dose reduction: Diarrhea Fatigue (0.8%) Asthenia (0.8%) Peripheral sensory neuropathy (0.6%) Septic shock (0.6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000MedR.pdf Page: p. 55
4 mg 1 times / week multiple, oral Recommended Dose: 4 mg, 1 times / week Route: oral Route: multiple Dose: 4 mg, 1 times / week Co-administed with:: lenalidomide(25 mg on Days 1 throughn21) dexamethasone(40 mg on Days 1, 8, 15, and 22 of a 28-day cycle) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000MedR.pdf Page: p. 56	unhealthy n = 360 Health Status: unhealthy Population Size: 360 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000MedR.pdf Page: p. 56	Disc. AE: Thrombocytopenia... AEs leading to discontinuation/dose reduction: Thrombocytopenia (8.6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000MedR.pdf Page: p. 56

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	substrate 1037	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 MRP2 383 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OCT2 647 MATE1 306 MATE2 263	CYP1A2 1054 CYP2B6 664 CYP2C8 693 CYP2C19 991 P-gp 1537 esterase 72	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no [IC50 >30 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no [IC50 >30 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no [IC50 >30 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no [IC50 >30 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no [IC50 >30 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no [IC50 >30 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no

Drug as victim

Target	Modality	Activity	Clinical evidence
esterase 72	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=9	major
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	minor
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	minor
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	minor
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	minor
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	weak
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	yes	unlikely Comment: Smoking is known to be a moderate CYP1A2 inducer. Based on population PK analyses of smokers in the Phase 3 Study C16010, smoking status (n=33 current smokers) was not found to be a significant covariate affecting ixazomib PK Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=8 Page: 8.0
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=5 Page: 5.0	yes	yes (co-administration study) Comment: Clinical DDI studies with strong CYP3A4 inhibitors ketoconazole and clarithromycin did not show clinically meaningful effects on ixazomib systemic exposure. On the other hand, clinical study with the strong CYP3A4 inducer rifampin showed significant decrease in ixazomib exposure (AUC v74%, CMAX \|54%). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf#page=5 Page: 5.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000PharmR.pdf#page=14 Page: 14.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90942	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90942
ChemicalBook	CB62521080	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62521080
MolPort	MolPort-016-633-297	https://www.molport.com/shop/molecule-link/MolPort-016-633-297
Selleck Chemicals	MLN-2238	http://www.selleckchem.com/products/MLN-2238.html
ZINC	ZINC000169946773	http://zinc15.docking.org/substances/ZINC000169946773
eMolecules	32278221	https://www.emolecules.com/cgi-bin/more?vid=32278221

PubMed

Title	Date	PubMed
Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer.	2010 Mar 1	20160034
Therapeutic landscape of carfilzomib and other modulators of the ubiquitin-proteasome pathway.	2015 Mar 1	25605842

Patents

Sample Use Guides

In Vivo Use Guide

Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15 of a 28-day cycle.

Route of Administration: Oral

In Vitro Use Guide

In a cell viability assay, MM.1S {Dexamethasone-(Dex) sensitive}, MM.1R (Dex-resistant), RPMI-8226, OPM1, OPM2, H929 and INA-6 (IL-6-dependent) human multiple myeloma cell lines were treated with various concentrations of ixazomib (6.25, 12.5, 25, 50 nM) for 48h. The anti-myeloma activity of the drug was observed in MM cell lines sensitive and resistant to conventional therapies, as well as representing distinct cytogenetic profiles.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 03:58:12 GMT 2023` Edited by `admin` on `Sat Dec 16 03:58:12 GMT 2023`
Record UNII	46CWK97Z3K
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

IXAZOMIB CITRATE

Official Name

English

IXAZOMIB CITRATE [JAN]

Common Name

English

IXAZOMIB CITRATE [MI]

Common Name

English

MLN9708

Code

English

MLN-9708

Code

English

IXAZOMIB CITRATE [ORANGE BOOK]

Common Name

English

Ixazomib citrate [WHO-DD]

Common Name

English

NINLARO

Brand Name

English

2,2'-(2-((1R)-1-((N-(2,5-DICHLOROBENZOYL)GLYCYL)AMINO)-3-METHYLBUTYL)-5-OXO-1,3,2-DIOXABOROLANE-4,4-DIYL)DIACETIC ACID

Systematic Name

English

IXAZOMIB CITRATE [USAN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2160