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Observational Study;
Midazolam as CYP3A phenotyping probe to investigate the effects of lapatinib on hepatic CYP3A activity.



- candidate number2760
- NTR NumberNTR1064
- ISRCTNISRCTN wordt niet meer aangevraagd
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR20-sep-2007
- Secondary IDsincomplete 
- Public TitleObservational Study;
Midazolam as CYP3A phenotyping probe to investigate the effects of lapatinib on hepatic CYP3A activity.
- Scientific TitleObservational Study;
Midazolam as CYP3A phenotyping probe to investigate the effects of lapatinib on hepatic CYP3A activity.
- ACRONYMN/A
- hypothesisLapatinib inhibits the function of Cytochrome P450 3A isoforms and P glycoprotein.
- Healt Condition(s) or Problem(s) studiedCancer
- Inclusion criteria1. Any patient who is going to be treated with lapatinib (1,2501,500 mg once daily);
2. Age >= 18 years;
3. WHO performance status < 2.4;
4. Adequate renal and hepatic functions, as determined within two weeks before planned start of lapatinib treatment (bilirubin < 1.25xULN; aspartate and alanine transferases (ASAT and ALAT) < 2.5xUNL; alkaline phosphatase (Alk Phos) < 5xULN; serum creatinine 1.5xULN);
5.Written informed consent;
6. Complete initial work-up prior to the first midazolam hydroxylation test.
- Exclusion criteria1. Symptomatic CNS-metastases or a history of a psychiatric disorder that would prohibit the understanding and giving of informed consent;
2. Use of and/or unwillingness to abstain from grapefruit, grapefruit juice, star fruit, dietary supplements, herbal tea, herbals, and over-the-counter medication (except for acetaminophen (paracetamol) and ibuprofen) during the study period, starting 3 weeks before the first midazolam hydroxylation test and ending after the third test;
3. Use of and/or unwillingness to abstain from/absence of adequate alternatives of CYP3A, CYP2C8, CYP2C19, BCRP (ABCG2), and P-glycoprotein (ABCB1) modulating (inducing or inhibiting; see also: http://medicine.iupui.edu/flockhart/table.htm)45 co-medication during the study period, starting 3 weeks before the first midazolam hydroxylation test and ending after the third test;
4. Use of and/or unwillingness to abstain from hypnotics and anxiolytics during the study period, starting 2 weeks before the first midazolam hydroxylation test and ending after the third test;
5. Current and/or recent alcohol- and/or drug (both psycholeptics and psychodysleptics)-abuse;
6. Use of and/or unwillingness to abstain from/absence of adequate alternatives of oxazepam, temazepam and midazolam during the study period, starting 3 weeks before the first midazolam hydroxylation test and ending after the third test.
- mec approval receivedno
- multicenter trialno
- randomisedno
- group[default]
- Type[default]
- Studytypeobservational
- planned startdate 1-jan-2008
- planned closingdate1-jul-2009
- Target number of participants15
- InterventionsPatients who will be treated with lapatinib as indicated will be asked to participate. Those patients who consent will undergo three midazolam hydroxylation tests: 12 days prior to their first administration of lapatinib and 78 and 2122 days after start of therapy. 2.5 mg of midazolam will be injected intravenously over a 15-30-second period. 5 mL blood samples will be collected pre-injection, and at 5 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, and 8h post-injection from an intravenous catheter.
- Primary outcomeCYP3A-activity, as determined by midazolam clearance tests.
- Secondary outcomeAuto-inhibition of lapatinib, as determined by lapatinib-levels.
- Timepoints
- Trial web site
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIES F.A. Jong, de
- CONTACT for SCIENTIFIC QUERIES F.A. Jong, de
- 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
- Publications
- Brief summaryIn the here-proposed study, we intend to study the in vivo effects of lapatinib on hepatic CYP3A activity, using midazolam as a probe drug. Patients who will be treated with lapatinib as indicated (not combined with any anti-cancer treatment known to modulate (that is inhibit or induce) drug metabolizing enzymes and drug transporters involved in lapatinib elimination) and who are not using any other concomitant medication/substance known to modulate CYP3A-activity, will be asked to participate. Those patients who consent to participate will undergo three midazolam hydroxylation tests: 12 days prior to their first administration of lapatinib and 78 and 2122 days after start of therapy (that is, on days they are normally seen for a routine check-up). Knowledge of the in vivo effects of lapatinib on hepatic CYP3A-activity in humans is of utmost importance and may reduce the risk of unintended adverse effects when other (anti-cancer) drugs that are metabolized by CYP3A are concomitantly used with lapatinib. In addition, knowledge of the in vivo effects of lapatinib on the functional expression of hepatic CYP3A may a priori optimize (future) study-protocols investigating combinations of this drug with CYP3A (anti-cancer) substrates characterized by a small therapeutic window.
- Main changes (audit trail)
- RECORD20-sep-2007 - 12-nov-2008


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