PharmacoKINEtics of TAMoxifen and its metabolites in breast cancer patients: the influence of a dose increase in phenotypic poor metabolizers of CYP2D6 (KINETAM)

Although already some information is available on the importance of CYP2D6
polymorphisms and/or the use of CYP2D6 inhibitors as co-medication that may
influence the treatment outcome of tamoxifen, this information does currently
not lead to a change in the management of this patient population. All women on
tamoxifen receive the standard dose of 20mg QD, irrespective of the use of
potential CYP2D6 inhibitors, and are not tested for CYP2D6 polymorphisms prior
to start of tamoxifen treatment.

Possible explanations (in random order) for this apparent discrepancy are:
- Conflicting results from the various studies on the importance of CYP2D6
polymorphisms and CYP2D6 inhibitors
- Few or no information on the actual plasma levels of endoxifen in these
studies
- Use of CYP3A inhibitors not taken into account (see figure 1)
- The relative potency of CYP2D6 inhibitors has not been formally assessed, let
alone its influence on tamoxifen pharmacokinetics.
- Other factors that may influence tamoxifen activation are usually not
included in the analyses, such as body weight, adherence, etc. For instance,
patients with depression could be less adherent, and therefore benefit less
from tamoxifen treatment; this effect could be unrelated to the use of
antidepressants in these women.
- Any factor that might be important is usually only studied as a single
determinant; for instance, we are aware of only one study in 80 women that has
looked at both CYP2D6 and use of CYP2D6 inhibitors simultaneously [6].
- Most importantly, to our knowledge, no information is available that dose
adjustments in women who are phenotypically poor metabolizers of tamoxifen can
compensate for reduced formation of endoxifen

In an attempt to at least resolve some of these issues we propose a prospective
study in women taking tamoxifen at a dose of 20mg QD who are being followed at
several large oncology clinics in the south-eastern part of the Netherlands
(Nijmegen (CWZ & Radboud), Den Bosch, Harderwijk and Arnhem). In each woman,
information will be collected on endoxifen levels, CYP2D6 status, adherence and
use of co-medication. In women who are phenotypically poor metabolizers of
tamoxifen, a dose increase to 40mg QD will be applied and the effect of this
intervention on tamoxifen pharmacokinetics will be evaluated after 4 weeks.

Primary:
To evaluate the effect of a dose increase to 40mg tamoxifen QD for 4 weeks in
patients with at least one CYP2D6 variant allele and/or the presence of a
CYP2D6 inhibitor

Secondary:
To evaluate the effect of concomitant use of (potential) CYP2D6
inhibitors/polymorphisms on the pharmacokinetics of tamoxifen and its
metabolites in breast cancer patients

This is an open-label, cross-sectional, multi-centre, phase-I, trial in 150
women who are being treated with tamoxifen 20mg QD.

After meeting the inclusion criteria and passing the exclusion criteria,
subjects will be sampled to determine the CYP2D6 status and plasma endoxifen
levels. Co-medication and adherence will be recorded based on the patient*s
information. In case of questions about the co-medication, and after approval
of the patient, the patient*s pharmacy will be contacted.

In case a CYP2D6 polymorphism and/or the presence of a CYP2D6 inhibitor is
found, a dose increase to tamoxifen 40mg QD will be applied and the patient
will return for measurement of the plasma endoxifen level 4 weeks later. After
this visit the patient can continue taking the normal dose (20 mg) of
tamoxifen.

In case a CYP2D6 polymorphism and/or the presence of a CYP2D6 inhibitor is
found, a dose increase to tamoxifen 40mg QD will be applied and the patient
will return for measurement of the plasma endoxifen level 4 weeks later. After
this visit the patient can continue taking the normal dose (20 mg) of
tamoxifen.

Patients may experience side-effects of a higher dose of tamoxifen than they
are use to using.
Venapuncture may cause discomfort and/or pain.