CYP3A4*22 genotype-guided dosing of TKIs in cancer patients: a new way of personalized therapy

CYP3A4 is part of the CYP enzyme family which is responsible for the metabolism
of 45-60% of the prescribed drugs. CYP3A4 forms the major part of the
cytochrome P450 enzyme family.

Wang et al. first described a new polymorphism in the CYP3A4 gene, rs35599367
or CYP3A4*22. CYP3A4*22 is caused by a transition from a cytosine into a
thymine in intron 6 which is located 192 bp upstream of exon 7 of the CYP3A4
gene (position 15389 in intron 6 of CYP3A4) which results in less activity of
CYP3A4 in the liver. Due to this transition the formation of a non-functional
splice variant (aSV) of CYP3A4 is increased. The partial retention of intron 6
result in the production of truncated CYP3A4 mRNA and therefore also less
production of full-length and functional CYP3A4 mRNA. The allelic frequency for
this SNP is 5,0% in Europeans, 2.6% in the admixed American population, 0,6% in
the South Asian population, 0% in East Asians and <0,1% in Africans.

In the preceding years several studies has been performed investigating the
effect of CYP3A4*22 on the pharmacokinetics of drugs metabolised by CYP3A4 in
patients diagnosed with cancer. A retrospective analysis in patients treated
with the TKI sunitinib showed a 22.5% decrease in the clearance of sunitinib in
CYP3A4*22 carriers versus non-carriers. Another study concluded that CYP3A4*22
carriers treated with the TKi pazopanib have a significant and clinical
relevant lower clearance and therefore higher exposure. Moreover, the performed
simulations showed that trough concentrations at steady state were 50% higher
in CYP3A4*22 carriers.

In short, in previous studies is proven that CYP3A4*22 results in a lower
clearance of TKIs metabolised by CYP3A4*22 and even can result in a higher
exposure when a drug is metabolised bij CYP3A4. A higher exposure can lead to a
higher incidence of toxicities caused by the drug. Due to this quality of life
could be lowered for a patient. Moreover, there is a chance that the treatment
for this patient has to be stopped because of the toxicity experienced by the
patient. If there is evidence that CYP3A4*22 carriers have at least the same
exposure when they are treated with a dosereduction of 25-33%, a relative
simple intervention could realize a effective treatment with a lower chance of
adverse events and toxicity.

To demonstrate that a dose reduction of 20-33% of CYP3A4 metabolized tyrosine
kinase inhibitors in patients expressing the CYP3A4*22 gene (rs35599367 C>T in
intron 6) does not result in a lower exposure (Ctrough) than the wildtype group
with the usual dose. If our hypothesis has been confirmed, in the future
CYP3A4*22 carriers could safely be treated with a lower dose without losing
exposure compared to non-carriers and most importantly, severe toxicity may be
prevented in CYP3A4*22 carriers.

Prospective multi-centre non-randomized non-inferiority intervention study

Patients intended to be treated with one of the participating drugs will be
prospectively genotyped for CYP3A4*22. Patients that prove to be wildtype will
be treated with the standard-dose treatment. In patients homozygous or
heterozygous polymorphic for CYP3A4*22 a 20-33% dose reduction during 3-4 weeks
(depending on drug) will be applied. Based on clinical tolerability and opinion
of the clinician the dose may be adjusted after the end of study.

In order to determine the CYP3A4*22 genotype prior to the start of therapy,
blood will be drawn from the patients which are intended to be treated with one
of the participating drugs and have signed the informed consent. This will not
require an extra venepuncture, as it is combined with other standard laboratory
pre-treatment tests. Therefore, the risk and burden associated with genotyping
is minimized.

The pharmacogenetic analysis may cause a small delay in the start of treatment.
However this analysis will be performed every week so this will be for a very
short period which is unlikely to be clinical relevant. Moreover between the
first visit and start of treatment patients are discussed in a
multidisciplinary board. In this period the logistics of the study could
already begin and the delay will be further reduced.

Since a dose reduction is performed there is a small risk patients are
underdosed. However, recent studies conclude that the exposure in CYP3A4*22
carriers is higher compared to wild type patients and therefore the risk that
patients are under dosed is limited. Moreover, the time of the dose reduction
is short (maximum of 4 weeks), dose reductions are often performed in clinical
practice in case of toxicity, we expect the same increase of drug exposure from
CYP3A4*22 carriers as from CYP3A4 inhibitors, which is from all the
participating drugs higher than a 25% increase and it is hypothesized that
genotype-guided dosing improves patient safety of treatment by reducing the
risk of severe toxicity and toxicity-associated hospitalization. Based on
clinical tolerability and opinion of the clinician the dose may be adjusted
after the end of study.

After steady state, a blood sample will be drawn for pharmacokinetic analysis.
There is no significant risk associated with this venepuncture, besides a small
risk of pain, bruises or thrombophlebitis, which is similar to the risk of
other venepunctures performed during routine treatment of the patient. If
possible, this venepuncture will be combined with a venepuncture for routine
care.