Inhibition of CYP2D6 enzymes by SSRIs may lead to reduced endoxifen plasma concentrations and thereby possibly influence tamoxifen treatment outcome. Paroxetine is a potent CYP2D6 inhibitor and strongly reduces endoxifen plasma concentrations.…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To determine the effects of switching from the potent CYP2D6 inhibitor
paroxetine to a weak CYP2D6 inhibitor (venlafaxine, escitalopram) on the
metabolism and plasma pharmacokinetics of tamoxifen and its metabolites in
breast cancer patients on tamoxifen therapy.
Pharmacokinetic parameters to be determined will include clearance (CL), area
under the plasma-concentration time curves (AUC), the maximum concentration
(Cmax) and time of Cmax (tmax).
Secondary outcome
- To compare toxic adverse effects in treatment courses with tamoxifen before
and after switching from a potent CYP2D6 inhibitor to a weak CYP2D6 inhibitor
(changes in adverse effects, severity of adverse effects).
Amendment:
Tertiary study parameters/outcome:
- To study the influence of antidepressants, other than paroxetine, which have
been shown to inhibit CYP2D6 in vitro and/or in vivo, on the pharmacokinetics
of tamoxifen (patient cases).
Pharmacokinetic parameters to be determined will include clearance (CL), area
under the plasma-concentration time curves (AUC), the maximum concentration
(Cmax) and time of Cmax (tmax).
Background summary
Tamoxifen reduces the risk of recurrence and of mortality, however, not all
women benefit from the tamoxifen therapy. In addition, treatment-related
adverse reactions (i.e. hot flashes) also vary greatly between patients.
Inter-individual variability in metabolism of tamoxifen, which is influenced by
both genetic and environmental factors, contributes to the differences in
efficacy and toxicity of tamoxifen.
Tamoxifen is metabolized into several metabolites, including endoxifen, which
is thought to be of most importance for the pharmacological activity of
tamoxifen treatment. The cytochrome P450 iso-enzyme CYP2D6 plays an important
role in the metabolism of tamoxifen. In addition to CYP2D6 genotype, use of
CYP2D6 inhibiting co-medication (e.g. antidepressants) may lead to reduced
endoxifen concentrations and thereby possibly influence tamoxifen efficacy.
Based on literature, it is recommended to avoid paroxetine in patients on
tamoxifen therapy and use antidepressants with little or no CYP2D6 inhibition
properties. Nevertheless, there is no direct evidence that switching from
paroxetine to weak CYP2D6 inhibiting SSRI/SNRIs will lead to higher endoxifen
concentrations. To establish drug-interactions, a direct comparison is
essential and of more value than indirect comparisons as conducted so far. In
this study we will examine the effects of switching from a potent CYP2D6
inhibitor (paroxetine) to a weak inhibitor of CYP2D6 (venlafaxine or
escitalopram). Patients will be their own control and are not allowed to use
drugs or supplements, known to interfere with the metabolism of tamoxifen. In
case of increased endoxifen concentrations in patients who switched from
paroxetine to venlafaxine or escitalopram, comparable with endoxifen
concentrations found in previous studies in patients without CYP2D6 inhibitors
(dependent on CYP2D6 genotype), we can conclude that venlafaxine and/or
escitalopram can be safely used along with tamoxifen.
Amendment: In addition to paroxetine, a strong CYP2D6 inhibitor, there are
several other antidepressants which have been shown to inhibit CYP2D6 and may
therefore also interfere with tamoxifen metabolism, leading to reduced
endoxifen concentrations. For a number of these antidepressants, evidence for
its safe use along with tamoxifen is lacking. In daily practice, physicians
have to treat patients with tamoxifen who already use other co-medication. In
some cases this co-medication has been shown to interact with CYP2D6, either in
vitro and/or in vivo. The question will arise whether this co-medication may
affect the metabolism of tamoxifen or not. As tamoxifen has to be converted
into its active metabolite endoxifen by CYP-mediated metabolism, it is
important to establish that particular co-medication does not affect the
metabolism of tamoxifen and its use in combination with tamoxifen is safe. For
that reason, patients with low endoxifen trough level (= endoxifen
concentrations belonging to the 25% lowest endoxifen concentrations in a group
of tamoxifen patients without CYP2D6 inhibitors, obtained from previous
studies) may be included in the switch study. Patients will be switched from
the current antidepressant to treatment with venlafaxine or escitalopram. The
findings can be described as patient cases (case report).
Study objective
Inhibition of CYP2D6 enzymes by SSRIs may lead to reduced endoxifen plasma
concentrations and thereby possibly influence tamoxifen treatment outcome.
Paroxetine is a potent CYP2D6 inhibitor and strongly reduces endoxifen plasma
concentrations. Venlafaxine, citalopram en escitalopram are considered to have
little or no effect on endoxifen plasma concentrations. Switching from
paroxetine to a weak CYP2D6 inhibiting SSRI (i.e. venlafaxine, escitalopram),
probably lead to higher endoxifen plasma concentrations.
In this study we will examine the effects of switching from a potent CYP2D6
inhibitor (paroxetine) to a weak inhibitor of CYP2D6 (venlafaxine,
escitalopram) on the metabolism and plasma pharmacokinetics of tamoxifen and
its metabolites in breast cancer patients on tamoxifen therapy.
Amendment: To study the influence of antidepressants, other than paroxetine,
which have been shown to inhibit CYP2D6 in vitro and/or in vivo, on the
pharmacokinetics of tamoxifen (patient cases).
Study design
This is a pharmacokinetic study intended to investigate the effects of
switching from the potent CYP2D6 inhibitor paroxetine to a weak inhibitor of
CYP2D6 on the plasma pharmacokinetics of tamoxifen and its metabolites. The
study will be performed at the Erasmus MC- Rotterdam. It is anticipated that
the study will be completed in 36 months. Thirteen evaluable patients, who are
treated with a dose of 20 or 40 mg tamoxifen and paroxetine, will be included
in this trial. Under careful supervision of a psychiatrist from the Erasmus MC,
patients will be switched from paroxetine (potent CYP2D6 inhibitor) to
treatment with a weak CYP2D6 inhibiting antidepressant (venlafaxine or
escitalopram). Depending on the indication of the SSRI and patient related
factors, either venlafaxine or escitalopram will be chosen as treatment.
SSRI/SNRI dose will be individually adjusted and adequate wash-out periods will
be applied in accordance with general guidelines. On day one (before switching)
and day 30 (after switching), PK samples will be taken as patients are
hospitalised for 24 hours.
Amendment: Patients who are/will be treated with tamoxifen in combination with
an antidepressant which has been shown to inhibit CYP2D6 in vitro and/or in
vivo may also be included in this study. First, an endoxifen trough level
(Ctrough) at steady state will be measured. In case of a low endoxifen
concentration (= endoxifen concentrations belonging to the 25% lowest endoxifen
concentrations in a group of tamoxifen patients without CYP2D6 inhibitors,
obtained from previous studies), patients may be included in the switch study.
The same treatment plan will be applied; patients who decide to participate in
the study will be switched (by a psychiatrist from the Erasmus MC) from the
current antidepressant to venlafaxine or escitalopram and will undergo two
24-hour pharmacokinetic sampling periods.
Intervention
Patients will be switched from paroxetine (potent CYP2D6 inhibitor) to
treatment with a weak CYP2D6 inhibiting antidepressant (venlafaxine or
escitalopram).
Amendment: Patients will be switched from the current antidepressant to
treatment with venlafaxine or escitalopram.
Study burden and risks
Patients are at risk of adverse effects of the newly started antidepressant
(venlafaxine or escitalopram). Worsening (temporary) of depression / anxiety
disorder or hot flashes may also occur. It is also possible that cessation of
paroxetine (Amendment: current antidepressant) will lead to withdrawal
symptoms. Since paroxetine (Amendment: current antidepressant) will be switched
to venlafaxine or escitalopram, under careful supervision of a psychiatrist,
withdrawal symptoms and possible worsening of depression, anxiety disorder or
hot flashes will probably not occur.
Endoxifen concentrations may increase after switching, which may contribute to
tamoxifen efficacy. In addition, the information may affect clinical decision
making (whether or not certain antidepressants will be prescribed to patients
on tamoxifen therapy.
's Gravendijkwal 230
3015 CE Rotterdam
NL
's Gravendijkwal 230
3015 CE Rotterdam
NL
Listed location countries
Age
Inclusion criteria
- Histological or cytological confirmed diagnosis of breast cancer, for which treatment with tamoxifen is indicated (to be evaluated by the treating physician);
- Use of tamoxifen for at least 4 weeks (to guarantee steady-state) and willing to continue the treatment until the end of the study;
- Concomitant use of paroxetine for at least 4 weeks (Amendment: or other antidepressant which has been shown to inhibit CYP2D6 in vitro/in vivo);
- Age > 18 years;
- WHO performance < 1;
- Adequate renal and hepatic functions (see protocol);
- Adequate hematological blood counts (see protocol);
- Written informed consent;
- No chemotherapy within the last 4 weeks before start;
- No radiotherapy within the last 4 weeks before start;
- No concurrent (over the counter) medication or (herbal) supplements, except SSRIs (Amendment: current antidepressant), known to induce or inhibit CYP2D6, CYP2C, CYP3A4 and/or P-glycoprotein;
- No concurrent medication or supplements which can interact with venlafaxine and/or escitalopram;
- Abstain from grapefruit, grapefruit juice, herbal dietary supplements, and herbal tea during the study.
Exclusion criteria
- Pregnant or lactating patients;
- Serious illness or medical unstable condition requiring treatment, symptomatic CNS-metastases or history of psychiatric disorder that would prohibit the understanding and giving of informed consent;
- Patients with a history of suicide attempts or current suicidal ideation;
- Contra-indications for venlafaxine and/or escitalopram use;
- Patients with Congenital Long QT Syndrome (CLQTS);
- Use of medications or dietary supplements known to induce or inhibit CYP2D6, CYP2C, CYP3A4 and/or P-glycoprotein;
- Unwillingness to abstain from grapefruit (juice), (herbal) dietary supplements, herbals, over-the-counter medication (except for paracetamol);
- More than one dose of tamoxifen (20 or 40 mg) per day;
- Non-compliance.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-002727-18-NL |
| CCMO | NL37224.078.11 |