Effects of dosing time on the pharmacokinetics and pharmacodynamics of sunitinib.

Since metabolism of sunitinib is dependant of different cytochrome P450
enzymes, including CYP3A4, which in cell-lines and rodents show a circadian
rhythm in expression, it is very likely that pharmacokinetics of sunitinib is
time dependant. The activity of CYP3A4 probably drops in night time. Higher
concentrations of sunitinib and its active metabolite may be reached when
sunitinibin the evening or afternoon.
This study is highly relevant, as sunitinib is a frequently used tyrosine
kinase inhibitor, without a clear advise on the intake times for this drug.
Higher levels of sunitinib and its active metabolite may result in better
anticancer effect. In a previous study, there was no increase in adverse events
when sunitinib was administered in the evening [17]. Therefore, it is safe to
administrate sunitinib in the evening, and potentially achieve a better
anticancer effect. We will compare the (plasma) pharmacokinetics of sunitinib
and its active metabolite N-desethyl-sunitinib at steady state when taken in
the morning to the pharmacokinetics when taken in the afternoon or evening. In
addition, we will closely monitor the side-effects (pharmacodynamics) during
all treatment cycles.
To investigate the circadian rhythm of CYP3A4, patients will be administered a
low dose of midazolam. Pharmacokinetics of midazolam and 1OH-midazolam will be
measured. In addition, also the endogenous marker 4beta-hydroxycholesterol will
be studied as an extra test to study CYP3A4 dynamics.

Primairy objective:
To investigate whether the pharmacokinetics of sunitinib are influenced by
circadian rhythm.

Secondary objective:
- to investigate whether daily variation in CYP3A4 activity exists in humans,
based on midazolam and 4beta-hydroxycholesterol PK.
- to investigate if evening dosing of sunitinib affects the side effects of
this drug.
- to investigate the influence of single-nucleotide polymorphisms in PK genes
on the exposure to sunitinib (based on the MEC02.1002 protocol).

This is a single center cross-over pharmacokinetic study intended to
investigate a circadian rhythm in sunitinib pharmacokinetics. The study will be
performed at the Erasmus MC, Daniel den Hoed Cancer Center. It is anticipated
that the study will be completed within 24 months. A total of 18 evaluable
patients will be treated with sunitinib at standard dosing of 50 mg once daily,
in a 4 weeks on, 2 weeks off scheme or a 37.5 mg continuous daily dose.
Patients will be deemed evaluable if blood withdrawal for pharmacokinetics is
completed at steady state in 1. one course when sunitinib is taken in the
morning and 2. in another course when sunitinib is taken in the evening. After
registration (see section 9), patients will be randomized to start in arm A
(50%) or arm B (50%). Patients in study arm A will start in the first course
after enrollment with sunitinib in morning dosing at 8.00 AM (+/- 1 hour), and
the second course in evening dosing at 06.00 PM (+/- 1 hour). Arm B will start
in the first course after enrollment with sunitinib in the evening at 06.00 PM
(+/- 1 hour), and the second course in the morning at 08.00 AM (+/-1 hour).
After switching from morning to evening dosing or vice versa, patients must use
sunitinib at this time point for at least 2 weeks. During the third course
patient will take sunitinib at 1 PM.
After completing these three courses, patients are free to decide at wich time
they will continue sunitinib intake.

Afternoon and evening intake of sunitinib in stead of morning intake of
sunitinib.

The burden for patients that participate in this study is low. Patients will be
hospitalized three times for 24 hours for PK sampling. PK samples will be taken
from an intravenous canule, so that patients don't need intravenous puncture
for every sample.
At one of the hospitalisations the PK samples will take place during the day.
At the other hospitalisation day, samples will be drawn in the evening and once
during the night. (For further information on sampling times, see protocol
Table 3)
The risk of participation in this study are low. Hematomas can occur when
removing the canule.
In a previous study, there was no increase in toxicity when sunitinib was
administered in the evening compared to the morning dose.