Ixazomib: Difference between revisions

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==Medical uses==
==Medical uses==
On November 20, 2015, the U.S. [[Food and Drug Administration]] approved ixazomib for use in combination with [[lenalidomide]] and [[dexamethasone]] for the treatment of multiple myeloma after at least one prior therapy.<ref>{{cite web|title=Press Announcements — FDA approves Ninlaro, new oral medication to treat multiple myeloma|url=http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm473771.htm|publisher=U.S. Food and Drug Administration|accessdate=24 April 2016|language=en}}</ref>
Ixazomib is used in combination with [[lenalidomide]] and [[dexamethasone]] for the treatment of multiple myeloma in adults after at least one prior therapy.<ref name="FDA">{{cite news|title=Press Announcements — FDA approves Ninlaro, new oral medication to treat multiple myeloma|url=http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm473771.htm|publisher=U.S. Food and Drug Administration|date=20 November 2015|language=en}}</ref><ref name="EMA">{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003844/WC500217620.pdf|title=Ninlaro: EPAR – Product Information|publisher=[[European Medicines Agency]]|date=21 November 2016}}</ref>

==Side effects==
Common side effects of the ixazomib+lenalidomide+dexamethasone study therapy included diarrhoea (42% versus 36% under [[placebo]]+lenalidomide+dexamethasone), constipation (34% versus 25%), [[thrombocytopenia]] (low [[platelet]] count, 28% versus 14%), [[peripheral neuropathy]] (28% versus 21%), [[nausea]] (26% versus 21%), [[peripheral oedema]] (25% versus 18%), vomiting (22% versus 11%), and back pain (21% versus 16%). Serious diarrhoea or thrombocytopenia occurred in 2% of patients, respectively.<ref name="EMA" /><ref name="AC" />

Side effects of ixazomib alone were only assessed in a small number of people. Diarrhoea grade 2 or higher was found in 24% of these patients, thrombocytopenia grade 3 or higher in 28%, and [[fatigue (medical)|fatigue]] grade 2 or higher in 26%.<ref>{{cite journal|title=Exposure–safety–efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study|doi=10.1007/s10637-016-0346-7|pmc=4859859}}</ref>


==Interactions==
==Interactions==
Ixazomib has a low potential for interactions via [[cytochrome P450]] (CYP) liver enzymes and [[transporter protein]]s. The only relevant finding in studies was a reduction of [[Cmax (pharmacology)|C<sub>max</sub>]] by 54% and of the [[area under the curve (pharmacokinetics)|area under the curve]] by 74% when ixazomib was combined with the strong [[CYP3A4]] inducer [[rifampicin]].<ref name="AC">{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2016|language=German}}</ref>
Ixazomib has a low potential for interactions via [[cytochrome P450]] (CYP) liver enzymes and [[transporter protein]]s. The only relevant finding in studies was a reduction of [[Cmax (pharmacology)|C<sub>max</sub>]] by 54% and of the [[area under the curve (pharmacokinetics)|area under the curve]] by 74% when ixazomib was combined with the strong [[CYP3A4]] inducer [[rifampicin]].<ref name="EMA" /><ref name="AC">{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2016|language=German}}</ref>


==Pharmacology==
==Pharmacology==
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===Pharmacokinetics===
===Pharmacokinetics===
[[File:Ixazomib citrate.svg|thumb|right|250px|alt=Ixazomib citrate—a prodrug for ixazomib|Ixazomib [[citrate]], the [[prodrug]] for ixazomib]]
[[File:Ixazomib citrate.svg|thumb|right|250px|alt=Ixazomib citrate—a prodrug for ixazomib|Ixazomib [[citrate]], the [[prodrug]] for ixazomib]]
⚫
The medication is taken orally in form of a [[prodrug]], ixazomib [[citrate]], which rapidly [[Hydrolysis|hydrolyzes]] under physiological conditions to its biologically active form, ixazomib.<ref name = "PI" /> Absolute [[bioavailability]] is 58%, and highest [[blood plasma]] concentrations are reached after one hour. [[Plasma protein binding]] is 99%.<ref name="AC" />


⚫
The medication is taken orally in form of a [[prodrug]], ixazomib [[citrate]], which rapidly [[Hydrolysis|hydrolyzes]] under physiological conditions to its biologically active form, ixazomib.<ref name = "PI" /> Absolute [[bioavailability]] is 58%, and highest [[blood plasma]] concentrations are reached after one hour. [[Plasma protein binding]] is 99%.<ref name="EMA" /><ref name="AC" />
⚫
The substance is metabolized by many CYP enzymes (''[[in vitro]]'': [[CYP3A4]] 42.3%, [[CYP1A2]] 26.1%, [[CYP2B6]] 16.0%, [[CYP2C8]] 6.0%, [[CYP2D6]] 4.8%, [[CYP2C9]] 4.8%, [[CYP2C9]] <1%) and non-CYP enzymes, which could explain the low interaction potential. [[Plasma half-life]] is 9.5 days, with 62% of ixazomib and its metabolites being excreted via the urine and 22% via the feces.<ref name="AC" />

⚫
The substance is metabolized by many CYP enzymes (''[[in vitro]]'': [[CYP3A4]] 42.3%, [[CYP1A2]] 26.1%, [[CYP2B6]] 16.0%, [[CYP2C8]] 6.0%, [[CYP2D6]] 4.8%, [[CYP2C9]] 4.8%, [[CYP2C9]] <1%) and non-CYP enzymes, which could explain the low interaction potential. [[Plasma half-life]] is 9.5 days, with 62% of ixazomib and its metabolites being excreted via the urine and 22% via the feces.<ref name="EMA" /><ref name="AC" />

==History==
On 20 November 2015, the U.S. [[Food and Drug Administration]] approved ixazomib combined with lenalidomide and dexamethasone for second-line treatment of multiple myeloma.<ref name="FDA" /> On 21 November 2016, the [[European Medicines Agency]] granted a conditional marketing authorisation for the same indication, requestion further efficacy studies.<ref name="EMA" />


==References==
==References==
{{reflist}}
{{reflist|35em}}


{{Chemotherapeutic agents}}
{{Chemotherapeutic agents}}
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[[Category:Orphan drugs]]
[[Category:Orphan drugs]]
[[Category:Takeda Pharmaceutical Company]]
[[Category:Takeda Pharmaceutical Company]]

{{antineoplastic-drug-stub}}

Revision as of 19:09, 4 January 2017

Ixazomib
Clinical data
Trade namesNinlaro
Other namesMLN2238
AHFS/Drugs.comninlaro
Routes of
administration		Oral (capsules)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability58%[1]
Protein binding99%
MetabolismHepatic (CYP: 3A4 (42%), 1A2 (26%), 2B6 (16%) and others)
Elimination half-life9.5 days
ExcretionUrine (62%), feces (22%)
Identifiers
  • N2-(2,5-Dichlorobenzoyl)-N-[(1R)-1-(dihydroxyboryl)-3-methylbutyl]glycinamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ECHA InfoCard100.238.319 Edit this at Wikidata
Chemical and physical data
FormulaC14H19BCl2N2O4
Molar mass361.03 g·mol−1
3D model (JSmol)
  • B([C@H](CC(C)C)NC(=O)CNC(=O)c1cc(ccc1Cl)Cl)(O)O
  • InChI=1S/C14H19BCl2N2O4/c1-8(2)5-12(15(22)23)19-13(20)7-18-14(21)10-6-9(16)3-4-11(10)17/h3-4,6,8,12,22-23H,5,7H2,1-2H3,(H,18,21)(H,19,20)/t12-/m0/s1
  • Key:MXAYKZJJDUDWDS-LBPRGKRZSA-N

Ixazomib (trade name Ninlaro) is a drug for the treatment of multiple myeloma, developed by Takeda. It acts as a proteasome inhibitor and has orphan drug status in the US.

Medical uses

Ixazomib is used in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in adults after at least one prior therapy.[2][3]

Side effects

Common side effects of the ixazomib+lenalidomide+dexamethasone study therapy included diarrhoea (42% versus 36% under placebo+lenalidomide+dexamethasone), constipation (34% versus 25%), thrombocytopenia (low platelet count, 28% versus 14%), peripheral neuropathy (28% versus 21%), nausea (26% versus 21%), peripheral oedema (25% versus 18%), vomiting (22% versus 11%), and back pain (21% versus 16%). Serious diarrhoea or thrombocytopenia occurred in 2% of patients, respectively.[3][4]

Side effects of ixazomib alone were only assessed in a small number of people. Diarrhoea grade 2 or higher was found in 24% of these patients, thrombocytopenia grade 3 or higher in 28%, and fatigue grade 2 or higher in 26%.[5]

Interactions

Ixazomib has a low potential for interactions via cytochrome P450 (CYP) liver enzymes and transporter proteins. The only relevant finding in studies was a reduction of Cmax by 54% and of the area under the curve by 74% when ixazomib was combined with the strong CYP3A4 inducer rifampicin.[3][4]

Pharmacology

Mechanism of action

Ixazomib is a peptide analogue that reversibly inhibits the protein proteasome subunit beta type-5 (PSMB5), which is part of the 20S proteasome complex.[4][6]

Pharmacokinetics

Ixazomib citrate—a prodrug for ixazomib
Ixazomib citrate, the prodrug for ixazomib

The medication is taken orally in form of a prodrug, ixazomib citrate, which rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib.[1] Absolute bioavailability is 58%, and highest blood plasma concentrations are reached after one hour. Plasma protein binding is 99%.[3][4]

The substance is metabolized by many CYP enzymes (in vitro: CYP3A4 42.3%, CYP1A2 26.1%, CYP2B6 16.0%, CYP2C8 6.0%, CYP2D6 4.8%, CYP2C9 4.8%, CYP2C9 <1%) and non-CYP enzymes, which could explain the low interaction potential. Plasma half-life is 9.5 days, with 62% of ixazomib and its metabolites being excreted via the urine and 22% via the feces.[3][4]

History

On 20 November 2015, the U.S. Food and Drug Administration approved ixazomib combined with lenalidomide and dexamethasone for second-line treatment of multiple myeloma.[2] On 21 November 2016, the European Medicines Agency granted a conditional marketing authorisation for the same indication, requestion further efficacy studies.[3]

References

  1. ^ a b "Ninlaro (ixazomib) Capsules, for Oral Use. Full Prescribing Information" (PDF). NINLARO (ixazomib) For Healthcare Professionals. Takeda Pharmaceutical Company Limited. Retrieved 21 November 2015.
  2. ^ a b "Press Announcements — FDA approves Ninlaro, new oral medication to treat multiple myeloma". U.S. Food and Drug Administration. 20 November 2015.
  3. ^ a b c d e f "Ninlaro: EPAR – Product Information" (PDF). European Medicines Agency. 21 November 2016.
  4. ^ a b c d e Haberfeld, H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  5. ^ "Exposure–safety–efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study". doi:10.1007/s10637-016-0346-7. PMC 4859859. {{cite journal}}: Cite journal requires |journal= (help)
  6. ^ KEGG: Ixazomib
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