Antineoplastic Agents

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Anti-Infective Agents

Sunitinib

Ketoconazole

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Sunitinib 50 mg administered as a single dose.

The drugs will be administered as follows:

* Sunitinib 37.5mg oral single dose.
* Ketoconazole 200 mg orally, once daily for 6 days. (Combination with sunitinib will be performed on day 4)

The drugs will be administered as follows:

* Sunitinib 37.5mg oral single dose.
* Ketoconazole 400 mg orally, once daily for 6 days. (Combination with sunitinib will be performed on day 4)

The drugs will be administered as follows:

* Sunitinib 25mg oral single dose.
* Ketoconazole 200 mg orally, once daily for 6 days. (Combination with sunitinib will be performed on day 4)

The drugs will be administered as follows:

* Sunitinib 25mg oral single dose.
* Ketoconazole 400 mg orally, once daily for 6 days. (Combination with sunitinib will be performed on day 4)

One capsule of sunitinib 50 mg orally. Single dose

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

Sunitinib and Ketoconazol

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

Sunitiinb and Ketoconazol

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

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

Enrique Grande Pulido

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

This is a phase I, pilot, open, randomized, parallel, and cross-over trial to assess the interaction between three different dose levels of sunitinib (50 mg, 37.5 mg, and 25 mg) and two dose levels of ketoconazole (200 mg and 400 mg) in 12 healthy volunteers (6 voluunteers in each group of treatment) 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

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

A Phase I, Pilot, Dose Finding Clinical Trial to Assess the Interaction Between Sunitinib and Ketoconazole to Reduce the Dose and Cost of Sunitinib for National Health System

On the fourth day of each period patient will be hospitalized in the clinical trial unit in order to obtain plasma concentrations previous to the administration of the corresponding dose and at the following times port-administration: 2h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 14h, 16h, 24h, 36h, 48h amd 72h. These measures will be calculated in order to describe the pharmacokinetic profile of each treatment arm.

To estimate the actual coefficient of variation of AUC and Cmax of sunitinib in our environment when given alone and in combination with ketoconazole.

An ECG to measure the QT interval will be performed coinciding with blood samples taken basal and at 6h, 8h, 10h, 12h and 72 h after drug administration in each period.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
To Assess the Interaction Between Sunitinib and Ketoconazole to Reduce the Dose and Cost of Sunitinib	NCT01548170	Cancer	Sunitinib Sunitinib and K... Sunitiinb and K... Sunitinib and K... Sunitinib and K...	18 Years - 35 Years	Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
To Assess the Interaction Between Sunitinib and Ketoconazole to Reduce the Dose and Cost of Sunitinib	NCT01548170	Cancer	Sunitinib Sunitinib and K... Sunitiinb and K... Sunitinib and K... Sunitinib and K...	18 Years - 35 Years	Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Spots Global Cancer Trial Database for interaction, phase i