Primary Objective: - to study the influence of administration aprepitant (Emend ®) on the clearance of fentanyl, in patients using a stable dose of the fentanyl patch (Durogesic ®).Stable dose is defined as using the same dose of fentanyl during at…
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
AUC, clearance
Secondary outcome
pain score (according Numerical Rating Scale)
side effects (according CTC toxicity criteria)
Background summary
Pain is a common problem in cancer patients, occurring both in curative
settings as well as in palliative settings. Opioids are often used to treat
cancer pain. Fentanyl is one of the most widely used opioids.
Several preparations of fentanyl are currently available (Kuip, J hosp ph).
The transdermal fentanyl patch is developed for maintenance medication in
chronic pain and is the most commonly used form. Patches are available in
different sizes, consistent with specific delivery doses of these patches
(12ug/hr, 25ug/hr, 50ug/hr, 75ug/hr or 100ug/hr). Fentanyl is absorbed through
the intact skin and a constant dose of drug is absorbed. Two different patches
have been developed; a reservoir patch and a matrix patch. These patches differ
in the way fentanyl is stored. However farmacokinetically, they are comparable
(Marier 2007 Br J clin pharm en Kress, Eur J Pharm biopharm 2010). Nowadays,
only the matrix patch is used in clinical practice.
After placement of the patch, the plasma fentanyl concentration gradually
increases. After 72hrs the patch has to be changed for a new one, as a stable
diffusion of the drug through the skin is no longer guaranteed. Steady state
concentrations are approached when a second transdermal fentanyl patch is
sticked on the skin (Portenoy 1993 Anesthesiology). Removing the patch will not
immediately lead to diminished fentanyl concentrations because of the amount of
fentanyl stored in subcutaneous depots, and therefore systemic concentrations
will gradually decrease.
Fentanyl is a drug that is highly lipophilic and binds strongly to plasma
proteins. Fentanyl is more potent than morphine at equipotent dose levels (Helm
2008 pain physician). The metabolism of fentanyl takes place primarily in the
liver (smith 2009 mayo clin proc). Fentanyl is mainly oxidized into the
inactive metabolite norfentanyl by the CYP3A4 iso-enzyme (Feierman Drug Metab
Dispos 1996). Less than 1% is metabolized to despropionyl-fentanyl,
hydroxyfentanyl, and hydroxynorfentanyl, which are also inactive metabolites.
Fentanyl is mainly excreted renally and for a minor part through the feces. The
large majority of the fentanyl is excreted as the metabolites mentioned; 10% as
unchanged drug (smith mayo clin proc 2009).
Unfortunately there is a wide pharmacokinetic intra- and interpatient
variability in patients using a fentanyl patch. It is largely unclear which
factors contribute to this variability (ref Van Nimmen/Solassol). It is crucial
to know which factors influence fentanyl concentrations because of the risk of
over- and underdosing of fentanyl. An overdose of fentanyl could lead to
serious complications, including respiratory depression or ultimately death,
while underdosing fentanyl may lead to inadequate pain relief.
Using different comedication next to the fentanyl patch can possibly lead to
interactions. It is important to know if these interactions can lead to changes
in fentanyl concentrations. Patients treated for cancer use often several
medications, like chemotherapy and medications to treat side effects of this
chemotherapy. Using different medications increase the risk for interactions.
Medication for treating nausea is widely used in cancer patients. Since 2005
aprepitant (Emend ®) registered in Europe as anti-emeticum. It is used for the
prevention of nauseau and vomiting associated with highly and moderately
emetogenic cancer chemotherapy (www.emea.europa.eu). Aprepitant is extensively
metabolized by CYP3A4 (Aapro, Annals Oncol 2010). It is known as a moderate
inhibitor for fentantanyl (www.drugs.com). In theory is is possible that the
combination of these medications may lead to an increase of the concentration
of fentanyl. This can lead to increasing side effects of fentanyl.
In this study we want to determine if administration of aprepitant (Emend ®)
influenced the pharmacokinetics of fentanyl.
Study objective
Primary Objective:
- to study the influence of administration aprepitant (Emend ®) on the
clearance of fentanyl, in patients using a stable dose of the fentanyl patch
(Durogesic ®).
Stable dose is defined as using the same dose of fentanyl during at least 8
days.
Study design
This is a single-center pharmacokinetic intervention study. The trial will be
performed at the Erasmus MC Cancer Institute, department of Medical Oncology.
Patients with a stable dosage of fentanyl used through a patch sticked at the
upper arm (once every 3 days), will be asked to participate. Patients will be
randomized over 2 arms, arm A and arm B. In arm A, patients will use aprepitant
125-80-80 mg (day 6, 7 and 8) concurrently with fentanyl, after which
pharmacokinetic sampling is performed (day 8). The pharmacokinetic sampling
will start 2 hours after the last intake of aprepitant. The fentanyl should
have been used for at least 8 days before the first pharmacokinetic sampling
period. A second pharmacokinetic sampling is taken in this arm, after another
period of at least 8 days. In arm B, aprepitant use is used prior to the second
pharmacokinetic sampling period.
Intervention
admission of 3 tablets aprepitant (125mg, 80mg, 80mg)
(according standard anti-emetic therapy in higly ematogenic chemotherapy)
Study burden and risks
na
Groene Hilledijk 301
Rotterdam 3075 EA
NL
Groene Hilledijk 301
Rotterdam 3075 EA
NL
Listed location countries
Age
Inclusion criteria
age >= 18
stable use of fentanyl patch
written informed consent
Exclusion criteria
using fentanyl as rescue medication
intolerance for aprepitant
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
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2013-002144-82-NL |
CCMO | NL45099.078.13 |
Other | NTC |