Clinical trial NCT05339672: Determining the Clinical Relevance of the Interaction Between Enzalutamide and the Opioid Morphine and the DOAC Edoxaban
Official title: Determining the Clinical Relevance of the Interaction Between Enzalutamide and the Opioid Morphine and the DOAC Edoxaban to Improve Rational Pharmacological Care of Patients With Prostate Cancer
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Drug-drug Interaction
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Astellas Pharma Inc
First posted: 2022-04-21
Enrollment: 26
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_CROSSOVER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with prostate cancer starting enzalutamide therapy

Brief summary: Enzalutamide is one of the oncolytic drugs that showed efficacy and safety in most of the features of prostate cancer. Approximately 17% of the patients treated with enzalutamide need pain control. Nearly all opioids are metabolized through one of the CYP enzymes induced by enzalutamide, making optimal pain management difficult. For pain control, while using enzalutamide, morphine is being advised since morphine is mainly glucuronidated by UGT2B7 and to a lesser extent UGT1A1. Enzalutamide is in vitro an inducer of UGT1A1 and may inhibit UGT2B7 which could alter morphine concentrations, though the clinical relevance of this interaction is unknown.

In patients with cancer, Direct Oral Anticoagulants (DOACs) are frequently used since vitamin-K antagonists were reported less effective than DOACs in preventing thromboembolic events. However, DOACs are all metabolized through CYP3A4 or P-gp. Due to interaction potential with DOACs, patients treated with enzalutamide are switched to Low Molecular Weight Heparin (LMWHs) administered subcutaneously which is considered safe but less patient friendly. For patients comfort DOACs are preferred over the use of LMWHs. Since rivaroxaban and apixaban are both major substrates for CYP3A4, combination with enzalutamide is prohibited. Dabigatran is a DOAC which is only metabolized by P-gp and edoxaban is a minor substrate for CYP3A4. Therefore, both might be safe to combine with enzalutamide. However, in patients with an active malignancy edoxaban is preferred according to national guidelines. Still, it is unknown if enzalutamide has a significant effect on the edoxaban exposure.

The purpose of this study is to evaluate the effect of enzalutamide on morphine and edoxaban pharmacokinetics.


Eligibility criteria: Inclusion Criteria:

* Patients with prostate cancer who will start treatment with enzalutamide within label
* Patients who are on treatment with opioids and/or therapeutic anticoagulation, that are treated with or willing and able to switch to morphine (2 dd extended release equivalent dose) and/or edoxaban (30mg or 60mg OD, according to the label)
* Age at least 18 years
* Patients who are able and willing to give written informed consent prior to screening
* Patients from whom it is possible to collect blood samples
* Life expectancy of \> 3 months
* Stable renal function and renal clearance \> 50ml/min

Exclusion Criteria:

* Patients who are co-treated with drugs that could interfere with the metabolism of enzalutamide, edoxaban and/or morphine

Primary outcomes:
measure: To determine the change in morphine and morphine-6-glucuronide exposure
timeFrame: 4-6 weeks after start of enzalutamide
measure: To determine the change in edoxaban and M4 exposure
timeFrame: 4-6 weeks after start of enzalutamide
Secondary outcomes:
measure: To evaluate the pain control in patients treated with and without enzalutamide and morphine
timeFrame: 4-6 weeks after start of enzalutamide
measure: To evaluate the safety of the combination of enzalutamide with edoxaban and/or morphine
timeFrame: 4-6 weeks after start of enzalutamide
measure: To evaluate the effect of edoxaban and/or morphine on enzalutamide exposure
timeFrame: 4-6 weeks after start of enzalutamide
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis en Vlietland hospital
Study officials:
References: