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| Clinical data | |
|---|---|
| Trade names | Ninlaro |
| Other names | MLN2238 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a616008 |
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| Routes of administration | By mouth (capsules) |
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| Pharmacokinetic data | |
| Bioavailability | 58%[4] |
| Protein binding | 99% |
| Metabolism | Hepatic (CYP:3A4 (42%),1A2 (26%),2B6 (16%) and others) |
| Eliminationhalf-life | 9.5 days |
| Excretion | Urine (62%), faeces (22%) |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
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| KEGG | |
| ChEBI | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.238.319 |
| Chemical and physical data | |
| Formula | C14H19BCl2N2O4 |
| Molar mass | 361.03 g·mol−1 |
| 3D model (JSmol) | |
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Ixazomib (trade nameNinlaro) is a drug for the treatment ofmultiple myeloma,[5] a type ofwhite blood cell cancer,[6] in combination with other drugs. It is takenby mouth in the form of capsules.
Common side effects include diarrhea, constipation and lowplatelet count. Like the olderbortezomib (which can only be given by injection), it acts as aproteasome inhibitor, hasorphan drug status in the US and Europe, and is aboronic acid derivative.
The drug was developed byTakeda. In the US, it is approved since November 2015, and in the EU since November 2016.
Ixazomib is used in combination withlenalidomide anddexamethasone 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.[7][8]
The study relevant for approval included 722 people. In this study, ixazomib increased themedian time ofprogression-free survival from 14.7 months (in theplacebo+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%.[8][9]
A phase 3 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd versus placebo in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, with median PFS of 21.4 versus 9.7 months; in standard-risk patients, with median PFS of 20.6 versus 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p). PFS was also longer with IRd versus placebo- in patients with 1q21 amplification, and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification. IRd demonstrated substantial benefit compared with placebo in relapsed/refractory multiple myeloma patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities.[10]
Ixazomib and lenalidomide areteratogenic 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 itsmetabolites pass into the breast milk.[8][11]
Common side effects of the ixazomib+lenalidomide+dexamethasone study therapy included diarrhoea (42% versus 36% under placebo+lenalidomide+dexamethasone), constipation (34% versus 25%),thrombocytopenia (lowplatelet 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.[8][11]
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%, andfatigue grade 2 or higher in 26%.[12]
The drug has a low potential for interactions viacytochrome P450 (CYP) liver enzymes andtransporter proteins. The only relevant finding in studies was a reduction of ixazomib blood levels when combined with the strongCYP3A4 inducerrifampicin. TheCmax was reduced by 54% and thearea under the curve by 74% in this study.[8][11]
At therapeutic concentrations, ixazomib selectively and reversibly inhibits the proteinproteasome subunit beta type-5 (PSMB5)[11] with adissociation half-life of 18 minutes. This mechanism is the same as ofbortezomib, which has a much longer dissociation half-life of 110 minutes; the related drugcarfilzomib, by contrast, blocks PSMB5 irreversibly.Proteasome subunits beta type-1 andtype-2 are only inhibited at high concentrations reached in cell culture models.[13]
PSMB5 is part of the20S proteasome complex and has enzymatic activity similar tochymotrypsin. It inducesapoptosis, a type ofprogrammed 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.[11][14]
The medication is taken orally as aprodrug, ixazomib citrate, which is aboronic ester; this ester rapidlyhydrolyzes under physiological conditions to its biologically active form, ixazomib, a boronic acid.[4] Absolutebioavailability is 58%, and highestblood plasma concentrations of ixazomib are reached after one hour.Plasma protein binding is 99%.[8][11]
The substance is metabolized by many CYP enzymes (percentagesin vitro, at higher than clinical concentrations: 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,[8] which could explain the low interaction potential.Clearance is about 1.86 litres per hour with a wide variability of 44% between individuals, andplasma 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.[8][11]
Ixazomib is aboronic acid andpeptide analogue[14] like the older bortezomib. It contains a derivative of the amino acidleucine with thecarboxylic acid group being replaced by a boronic acid; and the remainder of the molecule has been likened tophenylalanine.[13] The structure has been found through a large-scale screening of boron-containing molecules.[13]
The drug was developed by Takeda. It got US and European orphan drug status for multiple myeloma in 2011, and forAL amyloidosis in 2012. Takeda submitted a USnew drug application for multiple myeloma in July 2015.[15] In September 2015, the U.S.Food and Drug Administration (FDA) granted ixazomib combined with lenalidomide and dexamethasone apriority review designation for multiple myeloma.[16] On 20 November 2015, the FDA approved this combination for second-line treatment.[7]
The request for marketing authorisation in Europe was initially refused by theEuropean Medicines Agency (EMA) in May 2016 due to insufficient data showing a benefit of treatment.[17] 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.[8]
 | This section needs to beupdated. Please help update this article to reflect recent events or newly available information.(October 2020) |
As of January 2017[update], ixazomib is also inPhase III clinical trials for the treatment of AL amyloidosis[18] andplasmacytoma of the bones,[19] and in Phase I/II trials for various other conditions.[20][21]
