Detailed explanation of the functions and efficacy of Ixazomib/Enleri

Ixazomib/Ixazomib is indicated in combination with Lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Studies have shown that ixazomib has anti-angiogenic activity and blocks osteoclastogenesis and osteoclast resorption.

Ubiquitin-Proteasome signaling regulates cell homeostasis and survival: it promotes protein degradation, activates the transcription factor nuclear factor (NF)-κB to regulate the expression of growth and angiogenic factors, and blocks apoptosis. The 20S proteasome catalytic core consists of the same α and β rings and is part of the proteasome.

Ixazomib is a selective, potent and reversible20S proteasome inhibitor. It preferentially binds to the β5 chymotrypsin-like proteolytic site with a half-maximal inhibitory concentration (IC50) value of 3.4 nmol/L. 4,5 At higher concentrations, ixazomib may inhibit the caspase-like (β1) and trypsin-like (α2) proteolytic sites.

Ixazomib has antimyeloma effects with time-dependent reversible proteasome inhibition. Ixazomib induces apoptosis in multiple myeloma cell lines in vitro. Ixazomib is cytotoxic in vitro against myeloma cells from patients who have relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide shows synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in a mouse xenograft model of multiple myeloma.

After oral administration, ixazomib is rapidly absorbed, with a Tmax of 1 hour. Based on population pharmacokinetic (PK) analysis, the average absolute oral bioavailability was 58%. The area under the curve (AUC) of ixazomib increased in a dose-proportional manner over the dose range of 0.2 to 10.6 mg. A food effect study in patients receiving a single 4 mg dose of ixazomib showed that a high-fat meal reduced the AUC of ixazomib by 28% and the Cmax by 69%.