To Assess the Interaction Between Sunitinib and Ketoconazole to Reduce the Dose and Cost of Sunitinib
Condition: Cancer
Study type: Interventional
Phase: Phase 1

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
    

Detailed description: 
      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
    

Intervention name(s): Sunitinib; Sunitinib and Ketoconazol; Sunitiinb and Ketoconazol; Sunitinib and Ketoconazol; Sunitinib and Ketoconazol
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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 capsule 37.5mg. Single dose Ketoconazol 1 tablet of 200mg administered daily during 6 days.; 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.
Intervention MeSH terms: Ketoconazole; Sunitinib
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Pharmacokinetic; Sunitinib; Ketoconazol; interaction, Phase I