Determining the Clinical Relevance of the Interaction Between Enzalutamide and the Opioid Morphine and the DOAC Edoxaban

Study Overview
=================
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.

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

Conditions
-----------------
Drug-drug Interaction

Intervention / Treatment
-----------------
* Other: Blood sampling - Pharmacokinetic assessment


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Morphine<br>The participating patients are treated with morphine before start of enzalutamide (according to label). | Other: Blood sampling - Pharmacokinetic assessment<br>* Two pharmacokinetic assessements will be performed (before start of enzalutamide and 4-6 weeks after start of enzalutamide). Each pharmacokinetic assessment consists of 9 samples (3mL blood)<br>|
| Edoxaban<br>The participating patients are treated with edoxaban before start of enzalutamide (according to label). | Other: Blood sampling - Pharmacokinetic assessment<br>* Two pharmacokinetic assessements will be performed (before start of enzalutamide and 4-6 weeks after start of enzalutamide). Each pharmacokinetic assessment consists of 9 samples (3mL blood)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the change in morphine and morphine-6-glucuronide exposure | Change in AUC0-12hr | 4-6 weeks after start of enzalutamide | 
| To determine the change in edoxaban and M4 exposure | Change in AUC0-24hr | 4-6 weeks after start of enzalutamide | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the pain control in patients treated with and without enzalutamide and morphine | Change in Numeric Rating Scale (NRS). The pain NRS is a single 11-point numeric scale, with 0 representing no pain and 10 representing extreme pain. | 4-6 weeks after start of enzalutamide | 
| To evaluate the safety of the combination of enzalutamide with edoxaban and/or morphine | monitored with CTC-AE v 5.0 criteria. | 4-6 weeks after start of enzalutamide | 
| To evaluate the effect of edoxaban and/or morphine on enzalutamide exposure | Change in Ctrough of enzalutamide | 4-6 weeks after start of enzalutamide |