Ixazomib

Mechanism of Action

Ixazomib falls under the drug class of proteasome inhibitors. The drug is made up of an alanine leucine dipeptide core, and it is specifically a reversible inhibitor of the 26S proteasome and inhibits the chymotrypsin-like subunit of the proteasome.[9][10] This action ultimately disrupts cellular homeostasis, leading to apoptosis of multiple myeloma cells sensitive or resistant to other conventional therapies.[11]

Pharmacokinetics

Absorption: Following oral administration, ixazomib achieves maximum plasma concentration in 1 hour, with a mean oral bioavailability of 58%. The drug is highly protein-bound.

Distribution: The steady-state volume of distribution of ixazomib is 543 L.

Metabolism: The metabolism of ixazomib appears to occur via CYP and non-CYP pathways, with no predominant CYP isozyme contribution. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for ixazomib.[10] At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions (decreasing order) of 3A4, 1A2, 2B6, 2C8, 2D6, 2C19, and 2C9.[12]

Elimination: Ixazomib is eliminated mainly in the urine (62%) and the feces (22%). The drug has a terminal half-life of 9.5 days.

Administration

Dosage Forms and Strengths

Ixazomib is available in oral capsule formulations of 2.3, 3, and 4 mg. Ixazomib is orally dosed. 

Adult Dosing

The recommended dose is 4 mg per dose.[11] Based on the drug approval study, it should be taken weekly on days 1, 8, and 15 of a 28-day cycle.[3] 

It is also important to remember that ixazomib should be given with dexamethasone and lenalidomide, with specific dosing schedules within a cycle. Both ixazomib and dexamethasone are given on days 1, 8, and 15; it is important to separate them since ixazomib should not be taken with food, whereas dexamethasone should be.[1][11]

Ixazomib should be taken either 2 hours after eating or 1 hour before, with a full glass of water. The drug should be taken on the same day and hour of the week, and if a dose is missed, it should only be replaced if there are at least 72 hours till the next dose.[1][11]

Special Patient Population

Hepatic impairment: Ixazumib requires dose adjustment in patients with renal impairment. For patients with bilirubin >1.5 times the upper normal limit, start dosing at 3 mg daily on days 1, 8, and 15 of a 28-day cycle.[13]

Renal impairment: Renal impairment requires dose adjustment. For patients with a CrCl <30, start dosing at 3 mg daily on days 1, 8, and 15 of a 28-day cycle.

Pregnancy considerations: No human data is available; the risk of skeletal abnormalities, embryo-fetal toxicity, and reduced fetal weight exists based on animal studies. Clinicians should weigh the risks and benefits during pregnancy. Clinicians should obtain a pregnancy test before initiating treatment, and patients should avoid pregnancy using non-hormonal contraception methods during treatment and for 90 days following treatment cessation.

Breastfeeding considerations: Patients should avoid breastfeeding during treatment and for 90 days following treatment cessation.

Pediatric patients: Ixazomib is not approved for use in pediatric patients.

Older patients: Studies on older patients have shown that adding oral ixazomib to the standard treatment of lenalidomide and low-dose dexamethasone resulted in a clinically relevant progression-free survival benefit. However, this result did not include patients older than 75.[14]

Adverse Effects

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.[1] 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.

Different eye disorders were also seen in some patients taking ixazomib, including blurred vision, dry eyes, and conjunctivitis.[11] Furthermore, proteasome inhibitors are known to cause peripheral neuropathy, which was also seen with ixazomib. However, ixazomib caused fewer peripheral neuropathy cases than bortezomib, another proteasome inhibitor.[1]

Regarding nausea and vomiting that occurs with ixazomib, it was seen primarily in the first 3 months of treatment during the first cycle during the drug approval study. Antiemetics were added to the regimen in some cases, and some patients also received prophylactic antiemetics. The first instance of diarrhea was also highest during the first 3 months of treatment, and the occurrence decreased as time passed. Antidiarrheal medications were given to some patients, loperamide being the most common. In terms of constipation that occurred in some patients, the use of opioids due to bone pain as a possible cause cannot be ruled out. Rashes that occurred using ixazomib were commonly erythematous, macular, or papular lesions or generalized eruptions. Like nausea and diarrhea, the emergence of rashes was highest during the first 3 months of treatment and was managed with antihistamines, steroids, or dose reduction.[15]

Drug-Drug Interactions

Most drug interactions with ixazomib revolve around the effects of induced hepatic metabolism, leading to decreased levels of ixazomib. The list of such agents is long but includes bosentan, butalbital, carbamazepine, efavirenz, fosphenytoin, phenobarbital, phenytoin, and rifampin.

Contraindications

There are no specific contraindications to prescribing ixazomib. However, many warnings and precautions are necessary for patients taking this drug. For example, ixazomib should not be prescribed alongside cytochrome P3A inducers. Also, female patients should not take ixazomib during pregnancy due to the possibility of harming the fetus.[16]

Patients should avoid pregnancy while taking ixazomib, and contraception should be used while using the drug, as well as for the 90 days following the final dose of ixazomib. This measure applies to both males and females. Furthermore, due to the unknown effects of ixazomib on breast milk, the drug should be avoided in breastfeeding women. More caution is necessary for patients with renal or hepatic impairment as higher levels of ixazomib are circulating in the blood; clinicians should reduce the dose of ixazomib. In older patients, ixazomib can be dosed normally, as research has shown no differences between varying age populations. On the other hand, the safety and use of ixazomib in pediatric populations are unknown.[11]

Monitoring

Patients on ixazomib require close monitoring. Specifically, liver function tests need to be carried out periodically due to the risk of hepatotoxicity. There have been reports of patients taking ixazomib who experienced hepatic steatosis, hepatitis cholestatic, hepatocellular injury, and drug-induced liver injury. Hence, liver function must be monitored, and dose reductions must be made if necessary. Similarly, patients on ixazomib should have their platelets and absolute neutrophil count monitored monthly due to the risk of thrombocytopenia.

During the first 3 cycles of treatment with ixazomib, the platelet count should be monitored weekly as drug levels will not be stable. Dose modification can be considered if any adverse effects occur regarding platelet or neutrophil count. Do not start the medication unless ANC >1000 and platelet count >75,000. Lastly, patients on ixazomib should be monitored for any signs of infection, as reactivation of herpes zoster virus has been reported in some patients. To avoid this, patients should receive prophylactic antivirals while on ixazomib.[1][11][15]

Toxicity

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.[15] As previously discussed, there is also a risk of hepatotoxicity with ixazomib due to different hepatic injuries in patients; liver function monitoring is crucial.[11]

Furthermore, unlike other proteasome inhibitors previously reported to cause cardiac toxicity, ixazomib is not known to cause an increase in cardiac events, toxicities, or prolonged QTc interval.[15][17] Ixazomib is less neurotoxic than bortezomib and less cardiotoxic than carfilzomib.[2]

Enhancing Healthcare Team Outcomes

Ixazomib is currently the only oral proteasome inhibitor being used in treating multiple myeloma, so all interprofessional healthcare team members, including physicians, specialists, advanced practice practitioners, nursing staff, and pharmacists, should be aware of this drug, its indication, dosing, adverse event profile, potential drug-drug interactions, and requisite monitoring. Due to increasing use and the many adverse effects of ixazomib, the interprofessional team must monitor patients diligently, irrespective of their specific discipline. 

Clinicians must remember to monitor patients' liver function tests and platelet and neutrophil counts. The healthcare team should coordinate their activities and share information for patients on ixazomib if they are experiencing any rashes, feeling unwell, diarrhea, or other possible adverse reactions that dose modifications or other therapeutic alterations can be made in time. This interprofessional approach will increase the potential for patients to achieve success with their triple therapy, including dexamethasone and lenalidomide, and optimize outcomes in multiple myeloma cases.