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Induction of tamoxifen metabolism.


- candidate number9008
- NTR NumberNTR2709
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR24-jan-2011
- Secondary IDs2010-394  METC Erasmus MC, Rotterdam
- Public TitleInduction of tamoxifen metabolism.
- Scientific TitleOptimizing endoxifen concentration through the induction of CYP3A4, CYP2C and CYP2D6 mediated tamoxifen metabolism.
- ACRONYM
- hypothesisIn this randomized crossover pharmacokinetic study we will investigate the effects of cytochrome P450 enzyme induction (including CYP3A4, CYP2C and CYP2D6) by rifampicin on the metabolism and plasma pharmacokinetics of tamoxifen and its metabolites.
Induction of the expression of these CYP-enzymes will probably lead to an increased metabolism of tamoxifen into its (active) metabolites, including endoxifen. If it appears that endoxifen concentrations are significant higher after induction, there is a possibility created to increase endoxifen concentrations in future patients.
- Healt Condition(s) or Problem(s) studiedBreast cancer
- Inclusion criteria1. Histological or cytological confirmed diagnosis of breast cancer, for which treatment with tamoxifen monotherapy is indicated;
2. Use of tamoxifen monotherapy for at least 4 weeks (to guarantee steady-state) and willing to continue the treatment until the end of the study;
3. Age > 18 years;
4. WHO performance < 1;
5. Adequate renal and hepatic functions;
6. Adequate hematological blood counts;
7. Written informed consent;
8. No radiotherapy or chemotherapy within the last 4 weeks before start;
9. No concurrent (over the counter) medication or (herbal) supplements known to induce or inhibit CYP2D6, CYP2C, CYP3A4 and/or P-glycoprotein;
10. No concurrent medication or supplements which can interact with rifampicin;
11. Abstain from grapefruit, grapefruit juice, herbal dietary supplements, and herbal tea during the study.
- Exclusion criteria1. Pregnant or lactating patients;
2. Impossibility to take oral drugs;
3. 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;
4. Contra-indications for rifampicin and/or dextromethorphan use;
5. Use of medications or dietary supplements known to induce or inhibit CYP2D6, CYP2C, CYP3A4 and/or P-glycoprotein;
6. Unwillingness to abstain from grapefruit (juice), (herbal) dietary supplements, herbals, over-the-counter medication (except for low dose of paracetamol and ibuprofen) and other drugs known to seriously interact with CYP3A during the study period;
7. More than one dose of tamoxifen (20 or 40 mg) per day;
8. Non-compliance.
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingNone
- controlNot applicable
- groupCrossover
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-feb-2011
- planned closingdate1-feb-2012
- Target number of participants12
- Interventions1. Co-administration of 600 mg rifampicin during 15 days;
2. Dextromethorphan administration (during both clinical periods);
3. Pharmacokinetic sampling.
- Primary outcomeThe effects of cytochrome P450 enzyme induction (including CYP3A4, CYP2C and CYP2D6) by rifampicin on the metabolism and plasma pharmacokinetics of tamoxifen and its metabolites.
- Secondary outcome1. The effects of cytochrome P450 enzyme induction on the inter-patient variability in pharmacokinetics of tamoxifen and its metabolites;
2. The influence of genetic polymorphisms in enzymes involved in the metabolism of tamoxifen on the formation of endoxifen, in the presence and absence of rifampicin;
3. Incidence and severity of side effects in the presence and absence of rifampicin;
4. Validation of the previously developed dextromethorphan phenotyping test.
- Timepoints1. Prior to the study: Informed consent;
2. Day 1-15 (arm-A) / 3-17 (arm-B) co-administration of 600 mg rifampicin;
3. Day 15-16 (arm-A) / 17-18 (arm-B) pharmacokinetic sampling for 24 hours (after co-administration of rifampicin during 15 days);
4. Day 46-47 (arm-A) / 1-2 (arm-B) pharmacokinetic sampling for 24 hours (without rifampicin).
- Trial web siteN/A
- statusplanned
- CONTACT FOR PUBLIC QUERIES Lisette Binkhorst
- CONTACT for SCIENTIFIC QUERIESMD PhD Ron H.J. Mathijssen
- Sponsor/Initiator Erasmus Medical Center - Daniel den Hoed Kliniek, afdeling Interne Oncologie
- Funding
(Source(s) of Monetary or Material Support)
Erasmus Medical Center -Daniel den Hoed kliniek, afdeling Interne Oncologie
- PublicationsBinkhorst et al. Individualization of tamoxifen treatment for breast carcinoma. Clin Pharmacol Ther. 2012;92(1):62-7
- Brief summaryIn this randomized crossover pharmacokinetic study we will investigate the effects of cytochrome P450 enzyme induction (including CYP3A4, CYP2C and CYP2D6) by rifampicin on the metabolism and plasma pharmacokinetics of tamoxifen and its metabolites.
Induction of the expression of these CYP-enzymes will probably lead to an increased metabolism of tamoxifen into its (active) metabolites, including endoxifen. If it appears that endoxifen concentrations are significant higher after induction, there is a possibility created to increase endoxifen concentrations in future patients.
The study will be performed in one center (Erasmus Medical Center, Rotterdam, the Netherlands). Twelve patients who use tamoxifen monotherapy (20 or 40 mg) for at least 4 weeks (to guarantee steady state) will be included in this PK study. Patients will be co-treated with rifampicin during 15 days (1 tablet of 600 mg rifampicin per day). Before and after rifampicin co-administration, pharmacokinetic sampling will be performed during a 24 hour clinical period. Blood samples will be analysed by a validated liquid chromatography tandem mass spectometry method. The differences in pharmacokinetic parameters will be statistically evaluated using a paired Student's t-test.
- Main changes (audit trail)
- RECORD24-jan-2011 - 12-okt-2016


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