NINLARO 3 MG HARD CAPSULES

Indications

• Multiple myeloma (in combination with lenalidomide and dexamethasone)
• Targeted therapy-responsive malignancies

Dosage

Children: Refer to BNF for Children for paediatric dosing information.

Adults: Refer to BNF for specific dosing details, typically starting at 4 mg once weekly, with adjustments based on tolerance and side effects.

Mechanism of action

Ixazomib selectively binds to the β5 chymotrypsin-like site of the 20S proteasome, inhibiting its activity. This inhibition leads to the blockage of protein degradation, activation of NF-κB, and promotes the accumulation of pro-apoptotic factors, contributing to the induction of apoptosis in multiple myeloma cells. It also exhibits antiangiogenic properties and inhibits osteoclastogenesis.

Pharmacodynamics

Ixazomib demonstrates time-dependent reversible proteasome inhibition, which results in antimyeloma effects. It has shown to induce apoptosis in multiple myeloma cell lines, including those resistant to prior therapies. The drug exhibits synergistic effects when combined with lenalidomide, enhancing cytotoxicity. Additionally, in vivo studies have indicated its anti-tumor activity in models of multiple myeloma.

Pharmacokinetics

Ixazomib is administered orally and shows good bioavailability. It is metabolized primarily in the liver via CYP enzymes, and its elimination half-life allows for once-weekly dosing. Renal impairment may necessitate dose adjustments, particularly in patients with severe impairment. The drug's pharmacokinetics can be affected by concomitant medications that induce or inhibit metabolic pathways.

Adverse effects

• Back pain
• Constipation
• Diarrhoea
• Nausea
• Increased risk of infection
• Dizziness
• Fatigue
• Hypotension
• Blurred vision
• Appetite decreased
• Dry eye
• Conjunctivitis

Interactions

• St. John's Wort (decreases exposure)
• Mitotane (unknown effect on exposure)
• Rifampicin (unknown effect on exposure)

Precautions

• Monitor hepatic function regularly and adjust dose as necessary
• Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation
• Caution in hepatic impairment (risk of increased exposure)
• Caution in renal impairment (dose adjustments may be necessary)

Pregnancy

Manufacturer advises avoidance due to potential toxicity in animal studies.

Breast-feeding

Manufacturer advises avoidance, as no information is available.

Storage

Store in a cool, dry place, away from light.

Formulations

• Powder for solution for infusion

Mechanism of action

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.

Pharmacodynamics

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.