The primary objective of this study is to describe the pharmacokinetics (PK) of irinotecan, SN-38 and SN-38G in human by using apharmacokinetic compartment model .
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the study is to describe the pharmacokinetics of
irinotecan, SN-38 and SN-38G in plasma and in theintestines by using a
pharmacokinetic compartment model
Secondary outcome
To determine the beta-glucuronidase activity in fecal samples by an
enzym-activity assay
Background summary
Irinotecan is a commonly prescribed drug for the treatment of advanced
colorectal and pancreatic cancer. The metabolism of irinotecan consists of
multiple steps. Irinotecan is metabolized into the active metabolite SN-38 by
CES1 and CES2, present in the plasma, liver, and brain. Subsequently, SN-38 is
mainly inactivated by the liver enzyme UGT1A1, which converts SN-38 into
SN-38-glucuronide (SN-38G). The inactive metabolite SN-38G is excreted into the
intestines via bile. Hypotheses suggest that inactive SN-38G is reactivated by
bacteria that produce the enzyme called β-glucuronidase.
Various preclinical studies have investigated strategies to inhibit the
intestinal bacterial metabolite β-glucuronidase. However, as far as we know, no
studies have measured the concentrations of SN-38 and SN-38G in the human
intestinal tract to determine whether higher intestinal concentrations
correlate with higher plasma concentrations and whether higher intestinal
concentrations correlate with a higher presence of β-glucuronidase-producing
bacteria.
Therefore, more information about the pharmacokinetics of irinotecan in the
human intestines is needed. The aim of this study is to measure the intestinal
concentrations of SN-38 and SN-38G and to describe the pharmacokinetics as
comprehensively as possible using a NONMEM model. This descriptive pilot study
utilizes samples from ten patients being treated with irinotecan according to
standard procedure.
Study objective
The primary objective of this study is to describe the pharmacokinetics (PK) of
irinotecan, SN-38 and SN-38G in human by using apharmacokinetic compartment
model .
Study design
Descriptive, prospective, single centre, non-randomized pharmacokinetic pilot
study
Study burden and risks
The risk associated with participation in this clinical trial is considered low.
In order to determine blood concentrations of irinotecan, a total of 16 mL (4 x
4 mL per patient) of EDTA blood will be drawn from th epatients.The first
baseline blood draw is combined with the standard pre-therapy blood draw in the
week before the start of chemotherapy.
The second and third blood draws are taken via a single venipuncture using a
Venflon system. The blood draw at t=48h requires an additional
venapuncture.There is no significant risk associated with these venapunctures,
besides a small risk of thrombophlebitis, which is similar to the risk of other
venapunctures performed during routine treatment of the patient.
In order to determine faecal concentrations of irinotecan, five stool samples
are required. The patient collects the stool samples athome by using a standard
kit. The collection of stool samples for scientific research purposes is
considered as a minimally invasiveand non-burden some procedure for patients,
primarily due to the inherent nature of the task. Individuals routinely engage
in the natural process of defecation as part of their daily physiological
functions. The stool samples will be stored in the patient*s own freezer and
either handed in to at the clinician at the next visit or collected by the
coordinating researcher at the patient*s home.
While stool sampling is generally considered a low-risk procedure, it is
essentialto acknowledge the potential transmission of bacteria present in
faecal matter, which could lead to infections. However, the risk of infection
is mitigated by standard hygiene practices, which are explicitly mentioned in
the enclosed manual with the stool sampling kit
Michelangelolaan 2
Eindhoven 5623 EG
NL
Michelangelolaan 2
Eindhoven 5623 EG
NL
Listed location countries
Age
Inclusion criteria
• Pathologically confirmed malignancy for which treatment with irinotecan is
indicated at a dosing regimen of >= 180 mg/m2 in 2- or 3-weekly treatment
schedules.
• Patients who will start with their first cycle of treatment with chemotherapy
• Age >= 18 years
• Able and willing to give written informed consent
• Patient is able to temporarily store fecal samples in their freezer
• WHO performance status 0-2
• Minimal acceptable safety laboratory values defined as:
o ANC of >= 1.5 x 109 /L
o Platelet count of >= 100 x 109 /L
o Hepatic function as defined by serum bilirubin <= 1.5 x ULN, ALAT and ASAT <=
2.5 x ULN; in case of liver metastases ALAT and ASAT <= 5 x ULN.
o Renal function (eGFR) >= 50 ml/min or creatinine <= 1.5 x ULN
Exclusion criteria
• Patients with recently performed intestinal surgery including colectomy
• Patients with known substance abuse, psychotic disorders, and/or other
diseases expected to interfere with study or the patient*s safety
• Patients with either a ileostomy, ascending colostomy or transverse colostomy
• Patients unable or unwilling to stop the use of (over the counter) medication
or (herbal)
supplements which can interact with irinotecan (e.g. by induction of inhibition
of CYP3A4)
• Patients with an inability to undergo additional blood sampling.
• Patients with an inability to collect stool samples at home (e.g.
disabilities or incontinency).
• Patients with an inability to read and understand the informed consent form
Design
Recruitment
metc-ldd@lumc.nl
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 |
|---|---|
| CCMO | NL87206.058.24 |