Sunitinib malate for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors.
BACKGROUND
Sunitinib was approved by the US Food and Drug Administration (FDA) on January 26, 2006, for the treatment of metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumor (GIST) in patients who have failed to respond to imatinib or were unable to tolerate it.


OBJECTIVE
This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of sunitinib; potential drug interactions; and the results of clinical trials evaluating its efficacy and tolerability.


METHODS
Pertinent literature was identified by searches of MEDLINE (1966-January 31, 2007), the American Society of Clinical Oncology abstracts database (2000-2007 annual meetings/symposia and previous meetings), and the FDA Web site (October 2006). Search terms included, but were not limited to, sunitinib, SUl1248, renal cell carcinoma, gastrointestinal stromal tumor, pharmacology, pharmacokinetic, adverse events, and clinical trial. Additional publications were found by scanning the reference lists of the identified articles.


RESULTS
Sunitinib is a potent inhibitor of multiple tyrosine kinase receptors. Its Tmax is reached within 6 to 12 hours, and food does not appear to affect its bioavailability. Sunitinib is metabolized by cytochrome P450 (CYP) 3A4 to an active metabolite, SU12662, which is further metabolized by CYP3A4 to an inactive moiety. The parent compound and active metabolite have similar biochemical activity and potency and reach similar plasma concentrations. Sunitinib and SU12662 have a tl/2 of 40 to 60 hours and 80 to 110 hours, respectively. Steady-state concentrations of both active entities are reached after 10 to 14 days of therapy. In a Phase III trial comparing sunitinib with interferon-alfa (IFN-00 as first-line therapy for mRCC, sunitinib was associated with a median progression-free survival of 11 months, compared with 5 months with IFN-cz (P < 0.001). A randomized, double-blind, placebo-controlled trial evaluating sunitinib as second-line therapy for GIST found a median time to progression of 28.9 weeks in the sunitinib arm, compared with 7 weeks in the placebo arm (hazard ratio = 0.28; P < 0.001). In Phase II trials, sunitinib also had anti-tumor activity in patients with breast cancer, neuroendocrine tumors, and non-small cell lung cancer. Further evaluation in these tumors, as well as in patients with acute myelogenous leukemia, may lead to expanded indications. The approved dose of sunitinib is 50 mg/d PO for 4 weeks, followed by a 2-week rest; this pattern is repeated until tumor progression or the occurrence of intolerable adverse effects. The most common clinical toxicities attributable to sunitinib include diarrhea, mucositis/stomatitis, hypertension, rash, skin discoloration, and altered taste, whereas commonly occurring laboratory abnormalities have been seen in association with gastrointestinal toxicity, renal toxicity, and hematologic toxicity. Of grade 3/4 toxicities occurring with sunitinib (which are relatively uncommon [<10%]), those that are clinically important include hypertension, diarrhea, fatigue, and hand-foot syndrome.


CONCLUSIONS
Sunitinib is a multiple tyrosine kinase receptor inhibitor approved for the treatment of mRCC and GIST. Evidence for long-term clinical benefit in renal cell cancer and other tumors awaits the results of ongoing trials.
Adams
Val R
VR
Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA. vadam0@email.uky.edu
Leggas
Markos
M
D000367:Age Factors; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002292:Carcinoma, Renal Cell / Q000150:complications / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D007774:Lactation; D008175:Lung Neoplasms / Q000188:drug therapy; D018358:Neuroendocrine Tumors / Q000188:drug therapy; D011247:Pregnancy; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000077210:Sunitinib