To Assess the Interaction Between Sunitinib and Ketoconazole to Reduce the Dose and Cost of Sunitinib

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

Conditions

• Cancer

Interventions

DRUG

Sunitinib

One capsule of sunitinib 50 mg orally. Single dose

DRUG

Sunitinib and Ketoconazol

Sunitinib capsule 37.5mg. Single dose Ketoconazol 2 tablets of 200mg administered daily during 6 days.

DRUG

Sunitiinb and Ketoconazol

Sunitinib capsule 37.5mg. Single dose Ketoconazol 1 tablet of 200mg administered daily during 6 days.

DRUG

Sunitinib and Ketoconazol

Sunitinib capsule 25mg. Single dose Ketoconazol 1 tablet of 200mg administered daily during 6 days.

DRUG

Sunitinib and Ketoconazol

Sunitinib capsule 25mg. Single dose Ketoconazol 2 tablets of 200mg administered daily during 6 days.

Sponsors & Collaborators

• Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

  lead OTHER

Principal Investigators

• Enrique Grande Pulido · Hospital Universitario Ramón y Cajal

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

35 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2011-04-30

Primary Completion

2011-07-31

Completion

2011-07-31

Countries

• Spain

Study Locations