To determine the influence of concomitant administration of tamoxifen and probenecid on tamoxifen and endoxifen(-glucuronide) 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
The primary endpoint of this study is the Area under the curve (AUC) of
endoxifen. The AUC of endoxifen during tamoxifen monotherapy will be compared
to the AUC of endoxifen during concomitant treatment of tamoxifen with
probenecid.
Secondary outcome
Secondary endpoints include the difference in AUC for tamoxifen and
endoxifen-glucuronide and other pharmacokinetic parameters of endoxifen,
tamoxifen and endoxifen-glucuronide (i.e. clearance, maximum concentration
(Cmax), minimal concentration (Ctrough) and time until maximum concentration
(tmax) and elimination half-life (t*)). Furthermore, an explorative analysis on
difference in side-effects per treatment phase will be performed.
Background summary
Many anti-cancer drugs, like tamoxifen, are metabolized through phase II
metabolism. Tamoxifen is a selective estrogen receptor antagonist, that is
frequently used in the treatment of breast cancer. It is metabolized in two
steps, through phase I metabolism (i.e. CYP3A4 and CYP2D6), into endoxifen,
which is the most important pharmacologically active metabolite. Next, it is
glucuronidated into its inactive excretable form (i.e. endoxifen-glucuronide )
through several UGT enzymes (UGT1A4, UGT1A8, UGT1A10 and UGT2B7). Several
pharmacogenetic studies show that functional polymorphisms in UGTs responsible
for tamoxifen metabolism, may lead to altered endoxifen levels. Endoxifen
levels of * 5.97 ng/mL (16 nM) are considered as therapeutic, and therefore
this threshold value is used in clinical practice. Poor and intermediate
metabolizers for CYP2D6 usually do not reach the threshold, even in case of
doubled tamoxifen doses.
Since probenecid is a potent multi UGT inhibitor, endoxifen concentrations may
be significantly (and clinically relevantly) increased when administered
concomitantly with probenecid. Therefore, in this study, probenecid is used as
a booster drug. In this exploratory study we will evaluate the impact of
probenecid on tamoxifen pharmacokinetics in patients with breast cancer, and
also being a poor or intermediate metabolizer phenotype for CYP2D6.
Study objective
To determine the influence of concomitant administration of tamoxifen and
probenecid on tamoxifen and endoxifen(-glucuronide) plasma concentrations
Study design
This is a 2-period, single arm, sequential, cross-over pharmacokinetic study.
Intervention
Eleven patients on steady-state tamoxifen treatment will start with tamoxifen
alone for 7 days, followed by tamoxifen with probenecid for 14 consecutive
days. Patients will be admitted to the hospital for blood sampling on days 7
and 21 of the study for pharmacokinetic analysis.
Study burden and risks
Patients with breast cancer will be treated with tamoxifen as standard of care.
Patients enrolled in this study will start in phase A with tamoxifen
monotherapy, followed by tamoxifen concomitantly with probenecid for 14
consecutive days in phase B. During the 24 hour pharmacokinetic measurement,
patients are admitted to the hospital twice for an overnight stay (2 times 24
hours), during which 14 pharmacokinetic blood withdrawals of 6 mL will be
performed. Major risks are not expected for tamoxifen, as tamoxifen is
registered as standard of care. Since probenecid is given in a standard dose
for a short period of time (14 days), no major risks are to be expected.
Nonetheless, we will carefully observe all included patients using a patient
diary and weekly phone or clinical appointment, during the whole study period.
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Listed location countries
Age
Inclusion criteria
1. Age * 18 years
2. Patients with a confirmed diagnosis of primary or advanced breast cancer,
who are on tamoxifen treatment for at least three months (steady state
concentration).
3. A CYP2D6 poor metabolizer or intermediate metabolizer phenotype
4. WHO performance * 1 (Appendix B)
5. Able and willing to sign the informed consent form prior to screening
evaluations
6. Willing to abstain from strong CYP3A4, CYP2D6, CYP2C9/2C19, UGT and P-gp
inhibitors or inducers, herbal or dietary supplements or other over-the-counter
medication besides paracetamol.
7. Adequate kidney function defined as: GFR > 50 ml/min/1.73 m2
Exclusion criteria
1. Pregnant or lactating patients
2. Patients with known impaired drug absorption (e.g. gastrectomy and
achlorhydria)
3. Use of drugs which may show an increased systemic exposure when taken
concomitantly with probenecid e.g. methotrexate, penicillin, cephalosporin or
chinolon antibiotics or NSAIDs.
4. Patients with known blood dyscrasias, porphyria, uric acid kidney stones or
until an acute gouty attack has subsided.
5. Known serious illness or medical unstable conditions that could interfere
with this study requiring treatment (e.g. HIV, hepatitis, Varicella zoster or
herpes zoster, organ transplants, kidney failure (GFR<30 ml/min/1.73 m2),
serious liver disease (e.g. severe cirrhosis), cardiac and respiratory
diseases)
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004854-27-NL |
| CCMO | NL72309.056.19 |
| OMON | NL-OMON29503 |