(R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutylboronic acid

Absorption

After oral administration, the time to reach maximum concentration in plasma was 1 hour. The mean absolute oral bioavailability is 58%.

Toxicity

Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients. Ixazomib can cause fetal harm when administered to pregnant women, and therefore it should also be advised to women of reproductive age to avoid becoming pregnant on ixazomib.

The Uses of (R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutylboronic acid

Ixazomib is a proteasome inhibitor that acts by preventing cell growth in solid tumours. It is an anticancer agent that is used to treat patients with multiple myeloma and is potentially neurotoxic.

Background

Ixazomib a second generation proteasome inhibitor (PI) and the first oral PI approved by the FDA in November 2015 for multiple myeloma treatment in combination with 2 other therapies (lenalidomide and dexamethasone) for patients who have received at least 1 prior therapy. It was found to have similar efficacy to bortezomib (the first PI approved for multiple myeloma therapy) in the control of myeloma growth and prevention of bone loss. Ixazomib citrate is marketed by Takeda Pharmaceuticals under the brand name Ninlaro, which is a prodrug that becomes quickly converted to its active metabolite, ixazomib, after administration.

Indications

Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Definition

ChEBI: A glycine derivative that is the amide obtained by formal condensation of the carboxy group of N-(2,5-dichlorobenzoyl)glycine with the amino group of [(1R)-1-amino-3-methylbutyl]boronic acid. The active metabolite of ixa omib citrate, it is used in combination therapy for treatment of multiple myeloma.

Pharmacokinetics

In vitro studies have shown ixazomib to induce apoptosis in multiple myeloma cells sensitive or resistant to other conventional therapies. In mouse xenograft models, ixazomib induced tumor growth inhibition.

Metabolism

Metabolism of ixazomib is expected to be by CYP and non-CYP pathways, with no predominant CYP isozyme contribution. 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%).