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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.
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.
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.
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.
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
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.
Necitumumab is infused intravenously over 60 minutes.
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.