To Assess the Interaction Between Sunitinib and Ketoconazole to Reduce the Dose and Cost of Sunitinib
Status:
Completed
Trial end date:
2011-07-01
Target enrollment:
Participant gender:
Summary
Sunitinib is an ATP competitive tyrosine kinase inhibitor of several membrane receptors
including VEGFR-1, -2, and -3, PDGFR-α and -β, c-KIT, CSF-1R, FLT-3, and RET. Through this
molecular mode of action, sunitinib is able to avoid tumoral angiogenesis and proliferation.
Sunitinib is already approved by the FDA, EMEA and AEMPS for the treatment of patients with
metastatic renal cell carcinomas and those with metastatic gastrointestinal stromal tumors
(GIST) with progression or intolerance to imatinib.
Suntinib has recently reported to be superior than placebo in terms of response rate (9.3%
vs. 0%; p<0.05), progression free survival (11.4 vs. 5,5 months; HR 0.41;p<0.05), and overall
survival (HR 0.40;p<0.05) when administered in a phase 3 trial to patients with advanced
pancreatic neuroendocrine tumors (NETs).
Sunitinib is an expensive drug that drains the budget of health public system therefore it
demands a rational drug use.
Sunitinib is metabolized by CYP3A4, that belongs to the P450 cytochrome system in the liver.
Most of the drug is eliminated in faeces and only 16% by urine. Sunitinib has no food-effect
when taken with meals. Pharmacokinetics parameters did not differ between cancer patients and
healthy volunteers.
Houk et al. Showed that the area under the curve of plasmatic concentration of sunitinib and
its active metabolite did correlate with clinical outcome. In other words, the higher plasma
concentration area under the curve the highest rates of radiological response, progression
free and overall survival rates.
Ketoconazol is an antifungal drug that inhibits the CY3A4 inducing an elevation of peak
plasma levels of other drugs administered simultaneously and that are metabolized by the same
system. In the labeling sheet of sunitinib it is said that ketoconazol induced a 49% and 51%
of increase of plasmatic sunitinib Cmax y AUC0-∞ when both drugs were administered together.
This fact makes that the investigatorspropose that by administering both drugs simultaneously
the investigators could reduce sunitinib dose by a lower metabolization with similar plasma
concentration. The dose reduction would impact in drug cost.
Here the investigators propose to determine the most optimal combination dose of sunitinib
(25 mg or 37.5 mg) and ketoconazol (200mg o 400mg) by which the investigators could have
plasmatic bioequivalent concentrations compared with single dose of sunitinib 50mg.
Each volunteer will be assigned to a treatment arm (Arm A and Arm B). Volunteers included in
Arm A will take: sunitinib 50 mg, sunitinib 37.5 mg + ketoconazole 200 mg and sunitinib 37.5
mg + 400 mg ketoconazole. Volunteers included in Arm B will take: sunitinib 50 mg, sunitinib
25 mg + ketoconazole 200 mg and sunitinib 25 mg + 400 mg ketoconazole
Phase:
Phase 1
Details
Lead Sponsor:
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal