The Influence of Genotype/Phenotype, Grapefruit Juice and Orange Juice on the Pharmacokinetics of Sunitinib (Sutent, SU011248) in Patient With Imatinib Resistant Gastrointestinal Stromal Cell Tumor (GIST) or Metastatic Renal Cell Carcinoma
This is a prospective pharmacokinetic study in two groups of 10 adult patients with
imatinib-resistant gastro-intestinal stromal cell tumor or metastatic renal cell carcinoma
treated with sunitinib for at least one month.
Patients are treated at the recommended United States Food and Drug Administration approved
schedule of oral sunitinib administered at 25-50 mg per day for 4 weeks, in cycles of six
weeks. Four weeks of treatment with sunitinib, 25-50 mg per day followed by a 2 weeks off
period. In the absence of disease progression, administration of sunitinib will continue.
Within one month of the start of the study, patients will be requested to refrain from
drinking grapefruit and orange juice. The study will take place in 1 sunitinib treatment
cycle of 6 weeks (4 weeks of treatment with sunitinib (week 1-4) and 2 weeks off period
(week 5 and 6). The grapefruit juice or orange juice will be administered 3 times per day
for 1 period of 3 days in the 4th week of treatment with sunitinib.
The first sunitinib (total drug) pharmacokinetics day will be performed after steady-state
sunitinib levels are reached, meaning at least 14 days after starting sunitinib 25 - 50 mg
per day treatment (week 3 in the treatment cycle of sunitinib). On this first
pharmacokinetic day a dose of midazolam 7.5 mg will be given at the same time as the
sunitinib dose, to observe the effect of sunitinib on CYP3A4 capacity. Before the second
pharmacokinetic day (day 28 of sunitinib treatment) the patient will drink 3 times a day a
glass of grapefruit juice or orange juice for three consecutive day.Patients will be
assigned either to a grapefruit juice or orange juice arm. On this second pharmacokinetic
day the patient again will use a dose of midazolam at the sam time as the sunitinib dose, to
observe the effect of grapefruit juice or orange juice on the metabolic capacity pf CYP3A4.
The third pharmacokinetic day will take place at the end of week 6 of the treatment cycle,
the second week of the 2 week off period. The patient will receive a single oral dose of
midazolam 7.5mg, followed by midazolam pharmacokinetics to determine the base-line CYP3A
phenotypic expression. Pharmacokinetic parameters based on measurement in plasma samples
will be compared between the treatment periods.
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label
The influence of grapefruit juice and orange juice on the steady state area under the curve (AUC) of sunitinib in cancer patients
Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. Additionally patients receive grapefruit juice on day 25-27 of treatment. To determine the influence of grapefruit juice, sunitinib pharmacokinetics (PK) will be assessed on PK day 1, which will be between treatment day 14-20 (without grapefruit juice) and on PK day 2 on day 28 of treatment (after taking grapefruit juice for 3 days).
Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)