Predictive value of drug elimination gene polymorphisms on clearance and dose adjustment of sunitinib (Sutent, SU11248) in patients with cancer

Sunitinib, a novel tyrosine kinase inhibitor (TKI), is used as a first line
treatment for renal cell cancer. Clearance of Sunitinib has a inter*patient
variability of 40%. In another TKI (imatinib) it has been shown that there are
drug disposition genes involved in the uptake, elimination and metabolisation
of imatinib. These genes determine the activity of certain influx pumps like
organic cation transporter 1 (OCT1), also efflux pumps like multi drug
resistance 1 (MDR1) (P-glycoprotein, ABCB1) protein as well as metabolising
enzymes like CYP3A4. The activity of these pumps and enzymes are predictors of
pharmacokinetics. There are genotype and phenotype tests availabe of these
pumps and enzymes. The use of these tests assists to determine metabolism and
elimination function of the liver in each patient. Imatinib is eliminated
mostly via the liver into the bile, as are most of the new TKIs. Some of these
studies have been performed by H. Gurney at Westmead Hospital. It has further
been shown that higher blood levels of imatinib are correlated with response to
the treatment. Importantly there is evidence for the development of acquired
pharmacokinetic resistance. This resistance is induced by the treatment itself
with an induction of increased drug elimination causing decreased drug
exposure. In other TKI toxicity, like rash, was correlated with response to the
treatment. There is only little known about sunitinib in regards to the
importance of drug disposition genes and predictors of response to treatment.
There is also limited information about mechanisms of drug resistance.
The treatment with sunitinib is given as a fixed dose with only dose reduction
in case of toxicity. But it seems to be more and more important that we are
aware of the possible factors influencing pharmacokinetics of medication to
prevent under* and over*dosing in the anti cancer treatment.

Primary: To observe the correlation between ABCB1 polymorphisms in Exons 13, 22
and 27 and the clearance of sunitinib at steady state.
Secondary:
- To determine whether ABCB1 genotype correlates with toxicity-adjusted dose of
sunitinib

- To determine the pharmacokinetics at steady state of the sunitinib
treatment.
- To examine correlations between ABCB1 genotype and toxicity grade according
to CTC
criteria.

- To examine the correlation between genotype haplotype of other drug
elimination genes, such as organic anion transporter proteins (OATP) and other
biliary efflux proteins such as MRP2, BCRP with sunitinib clearance and
toxicity adjusted dose.
- Correlation of drug elimination phenotype test (sestamibi liver scan and
Midazolam clearance) with sunitinib clearance

Patients with cancer treated with sunitinib will undergo several
drug-disposition tests like pharmacokinetics, drug clearance phenotype and
genotype tests within this prospective investigator driven, multicentre, phase
II study.
In detail the following procedures will be performed
* Pharmacokinetic sampling of sunitinib will be performed to determine the
clearance on day 1 of any treatment cycle and within the 4th week of treatment
* Midazolam clearance test as CYP3A phenotype test (drug-metabolism test):
After a single microdose of midazolam a single blood test will be taken before
the start of a treatment cycle of sunitinib and sometime within the 4th week of
the same treatment cycle.
* Sestamibi liver scan: efflux pump (ABCB1) phenotype test. Before start of a
treatment cycle and a second time sometime within the 4th week of a treatment
cycle, a bolus intravenous injection of sestamibi will be given. Radioactivity
in the liver region will be measured by a gamma camera during a 90-minute
period.
* A blood sample will be drawn and archived for DNA analysis of polymorphisms
like CYP 3A4, 3A5, ABCB1, ABCG2 and other drug disposition genes at any time.
* Clinical data collection

The main burden for the patient is the time the patient needs to spend in the
hospital for extra blood tests and the liver scan. But we have planned the
tests in a way that the time is minimized.
There is a very low chance of serious complications due to the study tests.
Silberstein et al. reported (J Nucleare Med. Vol.37, No.1,Jan.1996) non out of
all patient in USA during 1988 and
1994, injected with Tc*sestamibi, had a serious reaction to Tc*sestamibi. There
was only one case of rash.
Generally patients treated with cancer undergo routinely blood tests and
radiological tests. A broader understanding of drug disposition of sunitinib
will also give insight into the drug diposition of other TKIs. By understanding
the drug disposition we are able to optimise the use of medication with the
prevention of under and over dosing. This will result in a higher efficacy of
medication and reduction of costs involved in the care of drug induced
complications. Generally for all medication use, adverse drug reactions are
estimated in USA 1994 to have caused 2.2 million hospitalisations and over
100,000 deaths and is in the USA the 4th*6th leading cause of death. In the
United Kingdom 1 in 5 hospitalisations are attributed to adverse drug
reactions.
Even though there is no direct benefit for the patient out of this study,
neither is there an expected serious burden. The benefit of the study is to
gain the knowledge of drug disposition of sunitinib to be able to develop
simple tests to predict individual dosing. The benefit for the members of the
population to which the participants belong to, is the prospect of prevention
of under and over dosing based on to follow prospective comparative studies.