The primary objective is comparison of the CYP3A4 activity in medically castrated patients with prostate cancer with the CYP3A4 activity of male patients with other types of solid tumours. To evaluate the CYP3A4 activity, the PK of the CYP3A4…
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Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To compare the CYP3A4 activity in prostate cancer patients versus patients with
other types of solid tumours, by use of a midazolam phenotyping test
Secondary outcome
- To measure plasma concentrations of midazolam
- To determine metabolite pharmacokinetics of midazolam
- Since polymorphisms in genes encoding for CYP3A4 can be important
determinants in the pharmacokinetics of midazolam, single nucleotide
polymorphisms in these genes will be assessed retrospectively
- exploratory: to differentiate between hepatic and gastro-intestinal CYP3A4
activity by comparison of oral and intravenous midazolam PK
Background summary
The metabolizing enzyme cytochrome P450 (CYP) 3A4 is an important factor in
the pharmacokinetics (PK) of many (anticancer) drugs, including taxanes.
Recently, it has been reported that the PK of intravenous docetaxel are
different in patients with castration resistant prostate cancer, as compared to
patients with other types of solid tumours. Different phase I studies with the
oral docetaxel formulation ModraDoc006 in combination with ritonavir (denoted
as ModraDoc006/r), were conducted in our institute in patients with
hormone-sensitive prostate cancer, castration-resistant prostate cancer (CRPC)
and other types of solid tumours. The exposure to docetaxel and ritonavir after
administration of the same dose and schedule of ModraDoc006/r was substantial
lower in prostate cancer patients as compared to the patients with other types
of solid tumours.
The underlying mechanism for these observations remains to be elucidated. The
lower docetaxel exposure with IV and oral docetaxel treatment and the lower
ritonavir exposure with ModraDoc006/r treatment might be related to a higher
CYP3A4 activity in prostate cancer patients. Therefore, it is important to
directly compare the CYP3A4 activity with a phenotyping test in prostate cancer
patients and patients with other types of solid tumours.
As a potential cause for this, CYP3A4 activity might be altered by medical
castration. Franke et al. showed that the clearance of docetaxel was higher in
castrated versus non-castrated prostate cancer patients. However, comparison of
the CYP3A4 activity in the castrated versus the prostate cancer patients with
normal levels of testosterone showed no significant differences. However, this
was done in 6 CRPC patients, of which one patient had an extremely low CYP3A4
activity. The intravenous erytromycin breath test that was used in this study
only reflects the hepatic CYP3A4 activity and not the gastro-intestinal CYP3A4
activity. The latter is important in treatment with oral docetaxel
(ModraDoc006) in combination with ritonavir. Furthermore, erythromycin is also
a substrate for P-gp indicating that the erythromycin breath test might reflect
P-gp activity as well as CYP3A4 activity. Therefore, it is necessary to
evaluate prostate cancer patients with a phenotyping test that includes both
the hepatic and gastro-intestinal CYP3A4-activity.
Midazolam is one of the most frequently used test compounds used for evaluation
of CYP3A4 activity. Midazolam has several advantages over other CYP3A4 probes
such as erythromycin, dapsone, quinine, and nifedipine. First, midazolam is
selectively metabolized by CYP3A4. Furthermore, midazolam clearance after both
oral and intravenous administration is a widely accepted and validated metric
of CYP3A4 activity. Continuing, midazolam AUC and metabolite clearance to its
major metabolite 1-hydroxy midazolam correlate well with hepatic CYP3A content.
Also, midazolam PK are highly sensitive to changes in CYP3A4 activity.
Therefore, oral midazolam will be used in this study to further evaluate the
CYP3A4 activity in prostate cancer patients in comparison to patients with
other types of solid tumours. Both oral and intravenous midazolam will be used
to be able to differentiate between the gastro-intestinal and the hepatic
CYP3A4 activity.
Study objective
The primary objective is comparison of the CYP3A4 activity in medically
castrated patients with prostate cancer with the CYP3A4 activity of male
patients with other types of solid tumours. To evaluate the CYP3A4 activity,
the PK of the CYP3A4 substrate midazolam will be investigated after oral and
intravenous administration.
Study design
On day 1, oral midazolam (2 mg) will be administered, followed by PK sampling
until 8 hours postdose
On day 2, intravenous midazolam (1 mg) will be administered, followed by PK
sampling until 8 hours postdose
Intervention
On day 1, oral midazolam (2 mg) will be administered, followed by PK sampling
until 8 hours postdose
On day 2, intravenous midazolam (1 mg) will be administered, followed by PK
sampling until 8 hours postdose
Study burden and risks
Participation is based on motivation to help with scientific research and has
no personal benefit for patients. The burden consist of hospitalization time of
2 days (staying overnight is not obligated), insertion of a venous peripheral
infusion needle for pharmacokinetic sampling, and administration of oral and
intravenous midazolam. Complications of the venous infusion needle are
flebitis, bruising and bleeding. Possible side effects of midazolam are
sedation and drowsiness.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Male patients receiving anticancer treatment or supportive care within our
institute
• Group 1: histological or cytological proof of prostate cancer, for which the
treatment leads to castrate levels of testosterone, defined as <= 50 ng/dL (or <=
0.50 ng/mL or 1.73 nmol/L)
• Group 2: histological or cytological proof of cancer.
2. Considered fit for midazolam treatment as assessed by the treating physician.
3. Age >= 18 years.
4. Able and willing to give written informed consent.
5. Able and willing to undergo blood sampling for PK and pharmacogenetic
analysis.
6. Able and willing to comply with study restrictions and to remain at the
study center for the required duration.
7. Adequate bone marrow, hepatic and renal functions
Exclusion criteria
1. Concomitant use of medication, herbs or food which could influence the
pharmacokinetics of midazolam within 14 days or five half-lives of the drug
(whichever is shorter) before start of the study, consisting of (but not
limited to) CYP3A4-inhibitors/inducers. In particularly, use of enzalutamide,
bicalutamide and dexamethasone is not allowed within 14 days before start of
the study. The use of prednisolone is allowed at a maximum daily dose of 10 mg.
2. Current smokers or patients who stopped smoking within 7 days before study
allocation
3. Cachexia as evaluated by a modified Glasgow Prognostic Score (mGPS) of 2:
albumin <35 g/L and CRP >= 10 mg/L
4. Patients with a known psychological or physical condition and/or expected
poor prognosis, which in the opinion of the investigator, contra-indicates
hospitalization and/or participation in the study for the individual patient.
Design
Recruitment
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 | NL75583.031.20 |