Ixazomib

Danger

H360 (100%): May damage fertility or the unborn child [Danger Reproductive toxicity]

P203, P260, P263, P264, P270, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 29 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In large clinical trials of ixazomib combined with lenalidomide and dexamethasone, elevations in serum aminotransferase levels were common, occurring in ~10% of patients. However, values greater than 5 times the upper limit of normal (ULN) were rare, occurring in

The most common adverse reactions seen with ixazomib are thrombocytopenia, neutropenia, nausea, vomiting, diarrhea, constipation, rash, peripheral neuropathy, peripheral edema, and back pain. These effects occurred in more than 20% of patients in the TOURMALINE MM1 study, with the most common severe adverse effects being thrombocytopenia and diarrhea. Some of these adverse events can become serious, particularly hepatotoxicity, neuropathy, neutropenia, and thrombocytopenia, in addition to thrombotic microangiopathy, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, and Stevens-Johnson syndrome.

Some of the toxicities involved with ixazomib include hematological and hepatic toxicities. Hematological toxicities include thrombocytopenia, which was seen primarily during the first 3 months of treatment in the drug approval study. Platelets usually drop after a dose of ixazomib and then rise again before the next treatment cycle. Also, during the study, a small percentage of patients had to be taken off of ixazomib therapy due to thrombocytopenia. As previously discussed, there is also a risk of hepatotoxicity with ixazomib due to different hepatic injuries in patients; liver function monitoring is crucial.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Ixazomib exerts antimyeloma effects with time-dependent reversible proteasome inhibition. Ixazomib induced apoptosis of multiple myeloma cell lines in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumour activity in a mouse multiple myeloma tumour xenograft model. Studies show that ixazomib exhibits an antiangiogenic activity and blocks osteoclastogenesis and osteoclast reabsorption.

The ubiquitin-proteasome signalling pathway regulates cellular homeostasis and survival: It promotes protein degradation, activates the transcriptional factor nuclear factor (NF)-κB to upregulate the expression of growth and angiogenic factors, and blocks apoptosis. Made up of identical alpha (α)- and beta (β)-rings, the 20S proteasome catalytic core is part of the proteasome. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome. It preferentially binds to the β5 chymotrypsin-like proteolytic site with a half-maximal inhibitory concentration (IC50) value of 3.4 nmol/L. At higher concentrations, ixazomib may inhibit the caspase-like (β1) and trypsin-like (β2) proteolytic sites.

After the oral administration of a radiolabeled dose, ixazomib represented 70% of total drug-related material in plasma. Ixazomib undergoes both CYP- and non-CYP-mediated metabolism, which is reported to be the major drug clearance mechanism. The major biotransformation pathways include hydrolysis, deboronation, and N-dealkylation, with drug metabolites not expected to retain pharmacological activity. At clinically relevant ixazomib concentrations, in vitro studies using human cDNA-expressed cytochrome P450 isozymes showed that no specific CYP isozyme predominantly contributes to ixazomib metabolism. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).