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Hosp Pharm. 2016 May; 51(5): 362–366.
PMCID: PMC4896343

Drug Monographs: Ixazomib and Necitumumab

Fern E. Lawson, PharmD,* J. Aubrey Waddell, PharmD, FAPhA, BCOP, and Dominic A. Solimando, Jr, MA, FAPhA, FASHP, BCOP

Abstract

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: ten.tsacmoc@cvSxRcnO; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: ten.retrahc@ruofddaw.

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MECHANISM OF ACTION

Ixazomib is a 20S proteasome inhibitor that specifically binds to and inhibits the chymotrypsin-like site of the β5 subunit of the 20S proteasome.1 At higher concentrations, ixazomib also inhibits the β1 and β2 subunits of the 20S proteasome.2 In vitro, ixazomib has demonstrated induction of apoptosis of multiple myeloma cells, including activity against cells from patients with relapsed and refractory multiple myeloma.

PHARMACOKINETICS

Ixazomib pharmacokinetics follows a 3-compartment model with first-order elimination. Oral absorption is rapid, with a time to maximum concentration (Tmax) of approximately 0.5 to 2 hours. Absolute oral bioavailability is estimated to be between 58% and 62%.3,4 After a weekly 4 mg oral dose of ixazomib, day 15 plasma maximum mean concentration (Cmax) ranged from 43.9 to 73.6 ng/mL.5,6 The area under the time-concentration curve (AUC0–168 h) ranged from 1,250 to 1,610 h•ng/mL, and increased proportionally with increasing doses.5–7 The volume of distribution (Vd) of ixazomib is 543 L.3 Ixazomib is 99% bound to plasma proteins. Terminal elimination half-life ranges from 4 to 8 days, with mean clearance estimated at 1.9 L/h.4,7 Following weekly oral administration, the accumulation ratio of ixazomib is 2.4.5 Drug-drug interactions with strong CYP3A4 inhibitors and inducers suggest ixazomib is metabolized by multiple CYP enzymes and non-CYP proteins.3,8,9 Twenty-two percent of ixazomib is excreted in feces and 62% in urine.3 Selected therapeutic regimens of ixazomib appear in Table 1.

Table 1.
Selected therapeutic regimens of ixazomib

PREPARATION

  1. Follow institutional policies for handling hazardous medications when dispensing ixazomib.
  2. Ixazomib is available as 2.3 mg, 3 mg, and 4 mg capsules.
  3. The manufacturer recommends that the capsule should be swallowed whole with water.
  4. The manufacturer recommends the capsules not be crushed, chewed, or opened.3

STABILITY

  1. Store at room temperature below 30°C (86°F). Do not freeze.
  2. The manufacturer recommends that capsules be kept in the original blister pack until time of administration.3

ADMINISTRATION

  1. Ixazomib should be taken orally, once a week for 3 weeks of a 4-week cycle.
  2. Doses should be taken on the same day of each week at approximately the same time.
  3. Ixazomib should be taken on an empty stomach, at least 1 hour before or at least 2 hours after food.
  4. If a dose of ixazomib is missed, the dose may be taken as long as the next scheduled dose is greater than or equal to 72 hours away.

TOXICITIES

The data below are presented as toxicity rates for ixazomib plus lenalidomide and dexamethasone/lenalidomide and dexamethasone/ixazomib alone (NR = not reported). The combination of ixazomib plus lenalidomide and dexamethasone is the only US Food and Drug Administration (FDA)-approved use for ixazomib.

  • A. Cardiovascular: Embolism (all grades) 2%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; heart failure (all grades) 4%/3%/NR,11 (grade 3 or 4) 2%/2%/NR11; orthostatic hypotension (all grades) 2%/NR/NR10; peripheral edema (all grades) 18%/NR/NR,10 (grade 3 or 4) 2%/NR/NR.10
  • B. Constitutional: Dehydration (grade 3 or 4) 2%/NR/3%to14%,6,10,12(allgrades)2%/NR/16%,10,12 (grade 3 or 4) 2%/NR/3% to 14%6,10,12; fatigue (all grades) 16% to 52%/NR/42%,5,10,12 (grade 3 or 4) 9% to 12%/NR/13%5,10,12; pyrexia (all grades) NR/NR/16%.12
  • C. Dermatologic: Maculo-papular rash (grade 3 or 4) NR/NR/3% to 14%6,12; skin and subcutaneous tissue reactions (all grades) 35% to 54%/21%/35%,5,10–12 (grade 3 or 4) 4% to 14%/1%/3%.10–12
  • D. Endocrine/metabolic: Hyperglycemia (all grades) 6%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; hypokalemia (all grades) 7% to 14%/NR/NR,5,10 (grade 3 or 4) 8%/NR/NR10; hypophosphatemia (all grades) 10%/NR/NR,10 (grade 3 or 4) 6%/NR/NR.10
  • E. Gastrointestinal: Abdominal distention (all grades) 10%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; abdominal pain (grade 3 or 4) NR/NR/14%6; constipation (all grades) 26%/NR/NR10; decreased appetite (all grades) 10% to 19%/NR/35%,5,10,12 (grade 3 or 4) 2%/NR/13%10,12; diarrhea (all grades) 40% to 46%/36%/45%,5,10–12 (grade 3 or 4) 6% to 14%/2%/23%5,10–12; dysgeusia (all grades) 22%/NR/NR10; gastroesophageal reflux disease (all grades) 14%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; intestinal perforation (all grades) 2%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; nausea (all grades) 16% to 48%/21%/42%,5,10–12 (grades 3 or 4) 2%/0%/3%10–12; vomiting (all grades) 21% to 30%/11%/42%,5,10–12 (grade 3 or 4) 1% to 2%/1%/3%.10–12
  • F. Hematologic: Anemia (all grades) 14%/NR/23%,10,12 (grade 3 or 4) 4% to 9%/13%/6%5,10–12; decreased neutrophil count (all grades) 2%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; decreased platelet count (all grades) 4% to 12%/NR/NR,5,10 (grade 3 or 4) 2%/NR/NR10; decreased white blood cell count (all grades) 2%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; leukopenia (all grades) 12%/NR/16%,10,12 (grade 3 or 4) 6%/NR/10%10,12; lymphopenia (all grades) 6%/NR/16%,10,12 (grade 3 or 4) 4%/NR/10%10,12; neutropenia (all grades) 19% to 24%/NR/32%,5,10,12 (grade 3 or 4) 14% to 19%/16%/26%5,10–12; thrombocytopenia (all grades) 19% to 28%/NR/45%,5,10,12 (grade 3 or 4) 8% to 13%/5%/28% to 39%.5,6,10–12
  • G. Hepatic: Increased alanine aminotransferase (ALT) (all grades) 12%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; increased aspartate aminotransferase (AST) (all grades) 8%/NR/NR,10 (grade 3 or 4) 2%/NR/NR.10
  • H. Infection: Bone abscess (grade 3 or 4) 2%/NR/NR10; pneumonia (all grades) 2% to 6%/8%/NR,10,11 (grade 3 or 4) 2% to 6%/8%/NR.10,11
  • I. Musculoskeletal: Muscle spasms (all grades) 16%/NR/NR10; non-cardiac chest pain (all grades) 2%/NR/NR,10 (grade 3 or 4) 2%/NR/NR.10
  • J. Neurologic: Agitation (all grades) 2%/NR/NR10; dizziness (all grades) 16%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; insomnia (all grades) 12% to 32%/NR/NR,5,10 (grade 3 or 4) 2%/NR/NR10; peripheral neuropathy (all grades) 26% to 38%/21%/32%,5,10–12 (grade 3 or 4) 2% to 4%/2%/3%.10–12
  • K. Pulmonary: Dyspnea (all grades) 14%/NR/21%,6,10 (grade 3 or 4) 0%/NR/21%.6,10
  • L. Renal: Increased serum creatinine (all grades) 6%/NR/NR,10 (grade 3 or 4) 2%/NR/NR10; renal failure (all grades) 4%/6%/NR,11 (grade 3 or 4) 2%/3%/NR.5,11
  • M. Treatment-Related Mortality: Respiratory syncytial viral pneumonia 2%/NR/NR.10

DOSAGE MODIFICATIONS

  • A. Hepatic: For moderate hepatic impairment (total bilirubin greater than 1.5 to 3 times ULN) or severe hepatic impairment (total bilirubin greater than 3 times ULN), reduce ixazomib starting dose to 3 mg.3
  • B. Renal:
    1. For severe renal impairment (creatinine clearance less than 30 mL/min or patients on dialysis), reduce ixazomib starting dose to 3 mg.3
    2. May administer ixazomib without regard to timing of dialysis.3
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MECHANISM OF ACTION

Necitumumab is a fully humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets epidermal growth factor receptor (EGFR) and competes with natural ligands, preventing signaling and proliferation of EGFR-dependent tumor cells.13 This fully human monoclonal antibody (mab) has shown antibody-dependent cellular cytotoxicity in EGFR-expressing cancer cells in vitro.14

PHARMACOKINETICS

Necitumumab demonstrates nonlinear pharmacokinetics; clearance is not affected by body weight. The half-life (t½) of necitumumab is 5 days. Peak concentration (Cmax) after an 800 mg dose is 509 ± 100 mcg/mL and AUC0–inf 59,071 ± 16,571 mcg•h/mL. Estimated mean clearance at steady state is 14.1 mL/h. The elimination half-life of necitumumab is estimated at 14 days.13,14 Monoclonal antibodies are degraded via proteolytic enzymes into amino acids. The manufacturer believes that necitumumab is metabolized in a similar manner. Currently there are no trials that examine the metabolism or excretion of necitumumab.15

Selected therapeutic regimens of necitumumab appear in Table 2.

Table 2.
Selected therapeutic regimens of necitumumab

PREPARATION

  1. Follow institutional policies for preparation of hazardous medications when dispensing necitumumab.
  2. Use necitumumab injection, 16 mg/mL.
  3. Dilute the drug in 250 mL 0.9% sodium chloride (NS) injection for intravenous infusion.
  4. Do not freeze or shake the solution and do not dilute with other solutions.

STABILITY

  1. Store necitumumab vials in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze.
  2. Diluted solutions are stable for no more than 24 hours refrigerated at 2°C to 8°C (36°F to 46°F) and no more than 4 hours at room temperature of up to 25° (77°F).

ADMINISTRATION

Necitumumab is infused intravenously over 60 minutes.

TOXICITIES

The data below is presented as toxicity rates for necitumumab plus gemcitabine and cisplatin/gemcitabine and cisplatin/necitumumab alone (NR = not reported). The combination of necitumumab plus gemcitabine and cisplatin is the only FDA-approved use for necitumumab.

  • A. Constitutional: Fatigue (all grades) 44%/43%/35%,13,16 (grade 3 or 4) 7%/7%/0%13,16; hypersensitivity/infusion-related reaction (all grades) 1%/2%/NR,16 (grade 3 or 4) 0.3%/0%/NR16; pyrexia (all grades) NR/NR/35%.13
  • B. Dermatologic: Acne (all grades) NR/NR/55%,13 (grade 3 or 4) NR/NR/3%13; acneform dermatitis (all grades) NR/NR/10%13; dry skin (all grades) NR/NR/24%,13 (grade 3 or 4) NR/NR/7%13; pruritus (all grades) NR/NR/21%13; rash (all grades) 76%/10%/NR,16 (grade 3 or 4) 7%/0.4%/NR16; skin fissures (all grades) NR/NR/21%13; skin reactions (all grades) 3%/2%/NR,16 (grade 3 or 4) 1%/0.2%/NR.16
  • C. Endocrine metabolic: Hypokalemia (all grades) NR/NR/31%13; hypomagnesemia (all grades) 31%/16%/3%,13,16 (grade 3 or 4) 9%/1%/0%.13,16
  • D. Gastrointestinal: Diarrhea (all grades) 16%/11%/41%,13,16(grade3or4)2%/1%/0%13,16; nausea (all grades) NR/NR/10%.13
  • E. Hematologic: Anemia (all grades) 42%/46%/3%,13,16 (grade 3 or 4) 11%/11%/0%13,16; arterial thromboembolic events (all grades) 5%/4%/NR,16 (grade 3 or 4) 3%/2%/NR16; febrile neutropenia (all grades) 1%/1%/NR,16 (grade 3 or 4) 1%/1%/NR16; neutropenia (all grades) 43%/46%/NR,16 (grade 3 or 4) 24%/28%/NR16; thrombocytopenia (all grades) 22%/26%/NR,16 (grade 3 or 4) 10%/10%/NR16; venous thrombo-embolic events (all grades) 9%/5%/NR,16 (grade 3 or 4) 5%/2%/NR.16
  • F. Ocular: Conjunctivitis (all grades) 7%/2%/NR,16 (grade 3 or 4) 0.3%/0%/NR.16
  • G. Pulmonary: Interstitial lung disease (all grades) 1%/1%/NR,16 (grade 3 or 4) 0.2%/1%/NR.16
  • H. Treatment-Related Mortality: Arterial thromboembolic events 0.6%/0.2%/NR16; interstitial lung disease 0.2%/0%/NR16; venous thromboembolic events 0.2%/0.2%/NR.16

REFERENCES

1. Smith DC, Kalebic T, Infante JR. et al. Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies. Invest New Drugs. 2015;33(3):652–663. [PMC free article] [PubMed]
2. Richardson PG, Baz R, Wang M. et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014;124(7):1038–1046. [PubMed]
3. Cambridge, MA: Millennium Pharmaceuticals Inc.; 2015. Ninlaro [package insert]
4. Gupta N, Saleh M, Venkatakrishnan K. Flat-dosing versus BSA-based dosing for MLN9708, an investigational proteasome inhibitor: Population pharmacokinetic (PK) analysis of pooled data from 4 phase-1 studies. Blood. 2011;118(21) (abstract 1433). http://www.bloodjournal.org/content/118/21/1433. Accessed February 6, 2016.
5. Gupta N, Goh YT, Min CK. et al. Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian patients with relapsed/refractory myeloma: A phase 1 study. J Hematol Oncol. 2015;103(8):1–9. [PMC free article] [PubMed]
6. Merlini G, Sanchorawala V, Zonder JA. et al. MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis (AL): Results of a phase 1 study. Blood. 2012;120(21) (abstract 731). http://www.bloodjournal.org/content/120/21/731. Accessed February 5, 2016.
7. Kumar S, Bensinger WI, Reeder CB. et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory multiple myeloma: Results from a phase 1 dose-escalation study. Blood. 2011;118(21) (abstract 816). http://www.bloodjournal.org/content/118/21/816. Accessed February 4, 2016.
8. Gupta N, Venkatakrishnan K, Noe DA. et al. A drug-drug interaction between strong CYP3A4 inhibitor ketoconazole and ixazomib citrate (MLN9708), an investigational, orally active proteasome inhibitor, in patients with advanced solid tumors and lymphoma. J Clin Oncol. 2013;31(suppl) (abstract 2555). http://meetinglibrary.asco.org/print/1155866. Accessed February 5, 2016.
9. Gupta N, Hanley MJ, Venkatakrishnan K. et al. A phase 1 drug-drug interaction study between ixazomib, an oral proteasome inhibitor, and rifampin in patients (pts) with advanced solid tumors. Mol Cancer Ther. 2015;14(12 suppl 2) (abstract B147). http://mct.accrjournals.org/content/14/12_Supplement_2/B147.short. Accessed February 5, 2016.
10. Kumar SK, Berdeja JG, Niesvizky R. et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: An open-label phase 1/2 study. Lancet Oncol. 2014;15(13):1503–1512. [PubMed]
11. Moreau P, Masszi T, Grzasko N. et al. Ixazomib, an investigational oral proteasome inhibitor (PI), in combination with lenalidomide and dexamethasone (IRd), significantly extends progression-free survival (PFS) for patients (Pts) with relapsed and/or refractory multiple myeloma (RRMM): The phase 3 Tourmaline-MM1 study (NCT01564537) Blood. 2015;126(23) (abstract 727). http://www.bloodjournal.org/content/126/23/727.full.pdf. Accessed January 13, 2016.
12. Kumar SK, Bensinger WI, Zimmerman TM. et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014;124(7):1047–1055. [PubMed]
13. Kuenen B, Witteveen PO, Ruijter R. et al. A phase 1 pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies. Clin Cancer Res. 2010;16(6):1915–1923. [PubMed]
14. Portrazza [package insert] Indianapolis, IN: Eli Lilly and Company; 2015.
15. Zhao H, Dorff S, Li H. Clinical pharmacology and biopharmaceutics review(s) New drug application number: 125547Orig1s000. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125547Orig1s000SumR.pdf. Accessed February 8, 2016.
16. Thatcher N, Hirsch FR, Luft AV. et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763–774. [PubMed]
17. Kumar SK, Laplant B, Roy V. et al. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015;5:e338. http://www.nature.com/bcj/journal/v4/n8/full/bcj201560a.html. Accessed January 13, 2016. [PMC free article] [PubMed]
18. Paz-Ares L, Mezger J, Ciuleanu TE. et al. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): An open-label, randomized, controlled phase 3 study. Lancet Oncol. 2015;16(3):328–337. [PubMed]

Articles from Hospital Pharmacy are provided here courtesy of SAGE Publications