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==Interactions==
==Interactions==
The drug 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 ixazomib blood levels when combined with the strong [[CYP3A4]] inducer [[rifampicin]]. [[Cmax (pharmacology)|C<sub>max</sub>]] was reduced by 54% and the [[area under the curve (pharmacokinetics)|area under the curve]] by 74% in this study.<ref name="EMA" /><ref name="AC">{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2016|language=German}}</ref>
The drug 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 ixazomib blood levels when combined with the strong [[CYP3A4]] inducer [[rifampicin]]. The [[Cmax (pharmacology)|C<sub>max</sub>]] was reduced by 54% and the [[area under the curve (pharmacokinetics)|area under the curve]] by 74% in this study.<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==
===Mechanism of action===
===Mechanism of action===
Ixazomib selectively and reversibly inhibits the protein [[proteasome subunit beta type-5]] (PSMB5), which is part of the [[20S proteasome]] complex. PSMB5 has enzymatic activity similar to [[chymotrypsin]] and 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.<ref name="AC" /><ref name="KEGG">[[KEGG]]: [http://www.kegg.jp/entry/D10130 Ixazomib]</ref>
At therapeutic concentrations, ixazomib selectively and reversibly inhibits the protein [[proteasome subunit beta type-5]] (PSMB5)<ref name="AC" /> with a [[dissociation (chemistry)|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 subunit beta type-1|Proteasome subunits beta type-1]] and [[Proteasome subunit beta type-2|type-2]] are only inhibited at high concentrations reached in cell culture models.<ref name="Muz">{{cite journal|title=Spotlight on ixazomib: potential in the treatment of multiple myeloma|pmid=26811670|pmc=4714737|doi=10.2147/DDDT.S93602}}</ref>

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.<ref name="AC" /><ref name="KEGG">[[KEGG]]: [http://www.kegg.jp/entry/D10130 Ixazomib]</ref>


===Pharmacokinetics===
===Pharmacokinetics===
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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 of ixazomib are reached after one hour. [[Plasma protein binding]] is 99%.<ref name="EMA" /><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 of ixazomib 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%) as well as non-CYP enzymes,<ref name="EMA" /> 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 faeces.<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%) as well as non-CYP enzymes,<ref name="EMA" /> which could explain the low interaction potential. [[Clearance (pharmacology)|Clearance]] is about 1.86 litres per hour with a wide variability of 44% between individuals, and [[plasma half-life]] is 9.5 days. 62% of ixazomib and its metabolites are excreted via the urine (of which less than 3.5% in unchanged form) and 22% via the faeces.<ref name="EMA" /><ref name="AC" />


==Chemistry==
==Chemistry==
Ixazomib is a [[boronic acid]] and [[peptide]] analogue<ref name="KEGG" /> like the older bortezomib. It contains a derivative of the amino acid [[leucine]] with the [[carboxylic acid]] group having been replaced by a boronic acid; and the remainder of the molecule has been likened to [[phenylalanine]].<ref name="Muz" />
Ixazomib is a [[peptide]] analogue and a [[boronic acid]] derivative<ref name="KEGG" /> like the older [[bortezomib]].


==History==
==History==

Revision as of 09:13, 6 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%), faeces (22%)
Identifiers
  • N2-(2,5-Dichlorobenzoyl)-N-[(1R)-1-(dihydroxyboryl)-3-methylbutyl]glycinamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
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, a type of white blood cell cancer,[2] in combination with other drugs. It is taken by mouth in form of capsules.

Common side effects include diarrhoea, 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, and is a boronic acid derivative.

The drug was developed by Takeda. In the US, it is approved since November 2015, and in the EU since November 2016.

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. There are no experiences with children and youths under 18 years of age.[3][4]

The study relevant for approval included 722 people. In this study, ixazomib increased the median time of progression-free survival from 14.7 months (in the placebo+lenalidomide+dexamethasone study arm including 362 people) to 20.6 months (under ixazomib+lenalidomide+dexamethasone, 360 people), which was a statistically significant effect (p = 0.012). 11.7% of patients in the ixazomib group had a complete response to the treatment, versus 6.6% in the placebo group. Overall response rate (complete plus partial) was 78.3% versus 71.5%.[4]

Pregnancy and breastfeeding

Ixazomib and lenalidomide are teratogenic in animal studies. The latter is contraindicated in pregnant women, making this therapy regimen unsuitable for this group. It is not known whether ixazomib or its metabolites pass into the breast milk.[4][5]

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 (swelling; 25% versus 18%), vomiting (22% versus 11%), and back pain (21% versus 16%). Serious diarrhoea or thrombocytopenia occurred in 2% of patients, respectively.[4][5]

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%.[6]

Interactions

The drug 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 ixazomib blood levels when combined with the strong CYP3A4 inducer rifampicin. The Cmax was reduced by 54% and the area under the curve by 74% in this study.[4][5]

Pharmacology

Mechanism of action

At therapeutic concentrations, ixazomib selectively and reversibly inhibits the protein proteasome subunit beta type-5 (PSMB5)[5] 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.[7]

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.[5][8]

Pharmacokinetics

Ixazomib citrate—a prodrug for ixazomib
Ixazomib citrate (MLN9708), 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 of ixazomib are reached after one hour. Plasma protein binding is 99%.[4][5]

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%) as well as non-CYP enzymes,[4] which could explain the low interaction potential. Clearance is about 1.86 litres per hour with a wide variability of 44% between individuals, and plasma half-life is 9.5 days. 62% of ixazomib and its metabolites are excreted via the urine (of which less than 3.5% in unchanged form) and 22% via the faeces.[4][5]

Chemistry

Ixazomib is a boronic acid and peptide analogue[8] like the older bortezomib. It contains a derivative of the amino acid leucine with the carboxylic acid group having been replaced by a boronic acid; and the remainder of the molecule has been likened to phenylalanine.[7]

History

The drug was developed by Takeda. It got US and European orphan drug status in for multiple myeloma in 2011, and for AL amyloidosis in 2012. Takeda submitted a new drug application for multiple myeloma in July 2015.[9] 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.[3]

The request for marketing authorisation in Europe was initially refused by the European Medicines Agency (EMA) in May 2016 due to insufficient data showing a benefit of treatment.[10] After Takeda requested a re-examination, the EMA granted a marketing authorisation on 21 November 2016 on the condition that further efficacy studies be conducted. The approval indication is the same as in the US.[4]

Research

As of January 2017, ixazomib is also in Phase III clinical trials for the treatment of AL amyloidosis[11] and plasmacytoma of the bones,[12] and in Phase I/II trials for various other conditions.

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. ^ Raab, M. S.; Podar, K; Breitkreutz, I; Richardson, P. G.; Anderson, K. C. (2009). "Multiple myeloma". Lancet (London, England). 374 (9686): 324–39. doi:10.1016/S0140-6736(09)60221-X. PMID 19541364.
  3. ^ a b "Press Announcements — FDA approves Ninlaro, new oral medication to treat multiple myeloma". U.S. Food and Drug Administration. 20 November 2015.
  4. ^ a b c d e f g h i "Ninlaro: EPAR – Product Information" (PDF). European Medicines Agency. 21 November 2016.
  5. ^ a b c d e f g Haberfeld, H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  6. ^ Gupta, N; Labotka, R; Liu, G; Hui, A. M.; Venkatakrishnan, K (2016). "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". Investigational New Drugs. 34 (3): 338–346. doi:10.1007/s10637-016-0346-7. PMC 4859859.
  7. ^ a b "Spotlight on ixazomib: potential in the treatment of multiple myeloma". doi:10.2147/DDDT.S93602. PMC 4714737. PMID 26811670. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: unflagged free DOI (link)
  8. ^ a b KEGG: Ixazomib
  9. ^ "Takeda Submits New Drug Application for Ixazomib for Patients with Relapsed/Refractory Multiple Myeloma". Takeda. 14 July 2015.
  10. ^ "Questions and answers on refusal of the marketing authorisation for Ninlaro" (PDF). European Medicines Agency. 27 May 2016.
  11. ^ Clinical trial number NCT01659658 for "Study of Dexamethasone Plus Ixazomib (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis" at ClinicalTrials.gov
  12. ^ Clinical trial number NCT02516423 for "Ixazomib Citrate, Lenalidomide, Dexamethasone, and Zoledronic Acid or Zoledronic Acid Alone After Radiation Therapy in Treating Patients With Solitary Plasmacytoma of Bone" at ClinicalTrials.gov
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