Optimizing endoxifen concentration through the induction of CYP3A4, CYP2C and CYP2D6 mediated tamoxifen metabolism

Tamoxifen therapy has proven its efficacy over the last decades. However,
30-50% of the patients with adjuvant tamoxifen therapy experience a relapse or
even die as a consequence of breast cancer, which indicates individual
differences in response to tamoxifen therapy. Which patients will respond to
therapy and which patients are prone to develop tamoxifen-related side-effects
is largely unknown prior to therapy, which makes it important to develop good
predictive markers.

The formation of endoxifen is thought to be of most importance for the activity
of tamoxifen treatment. An altered metabolism may contribute to the
inter-individual variability in plasma concentrations of the active components
(i.e. endoxifen), which in turn, possibly may affect treatment response to
tamoxifen.

To create a better treatment outcome, it is probably neccesary to increase
endoxifen concentrations. However, it is yet unclear whether endoxifen plasma
concentrations will increase as result of a higher dose of tamoxifen. In case
of impaired metabolism, due to inactive CYP2D6 enzymes for example, doubling of
the tamoxifen dose will probably not lead to double endoxifen concentrations.
Furthermore, low endoxifen concentrations have also been observed in patients
using 40 mg tamoxifen. Not only the supply of substrate, but also enzyme
activity may be a rate limiting step for the metabolism of tamoxifen.
Theoretically, induction of the metabolism of tamoxifen would be another option
to achieve increased endoxifen levels.


Dextromethorphan was used as a putative phenotyping probe for tamoxifen
pharmacokinetics in a previous study. This phenotyping probe appeared to be a
better predictor of endoxifen exposure compared to CYP2D6 genotyping
(predicting values of the variability in tamoxifen pharmacokinetics are 52% and
23% respectively). This *phenotyping* strategy has to be validated.


Amendment:
Results of the interim-analysis showed that co-administration of rifampicin
resulted in strongly reduced plasma concentrations of tamoxifen as well as its
metabolites. Therefore, we decided to stop rifampicin co-administration in the
study. However, already informed patients can still participate in the study
for pharmacokinetic analysis, without the use of rifampicin. Patients will be
hospitalized once (during a 24-hour period) for pharmacokinetic blood sampling.
Only dextromethorphan will be administered to the patients (secondary study
objective).

- To examine the effects of cytochrome P450 induction by rifampicin on the
metabolism and pharmacokinetics of tamoxifen and its metabolites.

Induction of cytochrome P450 enzyme expression (including CYP3A4, CYP2C and
CYP2D6) by rifampicin will probably lead to an increased metabolism of
tamoxifen into its (active) metabolites, including endoxifen.The main goal of
this study is to see whether it is possible to induce the metabolism of
tamoxifen into endoxifen, irrespective of CYP2D6 genotype/phenotype. If it
appears that endoxifen concentrations are significant higher after induction,
there is a possibility created to increase endoxifen concentrations in future
patients. Higher endoxifen concentrations in these patients may possibly lead
to improved efficacy of tamoxifen therapy, which have to be evaluated in future
studies.

- To validate the previously developed dextromethorphan phenotyping test.


Amendment:
Only secondary study objective: - Validation of the previously developed
dextromethorphan phenotyping test.

Amendment:
Already informed patients will be hospitalized during 24-hour for
pharmacokinetic blood sampling (13 in total). Dextromethorphan will be
administrated to the patients during both hospitalisation periods of the study
for the validation of this *phenotyping* strategy.
Blood samples for genotyping will also be collected once during or before the
study period (MEC 02.1002 protocol).

Amendment:
- Dextromethorphan (30 mg, -base) administration.

Amendement:
Adverse effects of dextromethorphan administration may occur. However, the risk
of adverse effects is expected to be minimal and adverse effects are of minor
severity.