MIND THE GAP: Determining the Clinical Relevance of the Interaction Between Enzalutamide and the Opioid Morphine and the DOAC Edoxaban
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Morphine The participating patients are treated with morphine before start of enzalutamide (according to label). |
Other: Blood sampling - Pharmacokinetic assessment
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)
|
| Edoxaban The participating patients are treated with edoxaban before start of enzalutamide (according to label). |
Other: Blood sampling - Pharmacokinetic assessment
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)
|
Outcome Measures
Primary Outcome Measures
- To determine the change in morphine and morphine-6-glucuronide exposure [4-6 weeks after start of enzalutamide]
Change in AUC0-12hr
- To determine the change in edoxaban and M4 exposure [4-6 weeks after start of enzalutamide]
Change in AUC0-24hr
Secondary Outcome Measures
- To evaluate the pain control in patients treated with and without enzalutamide and morphine [4-6 weeks after start of enzalutamide]
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.
- To evaluate the safety of the combination of enzalutamide with edoxaban and/or morphine [4-6 weeks after start of enzalutamide]
monitored with CTC-AE v 5.0 criteria.
- To evaluate the effect of edoxaban and/or morphine on enzalutamide exposure [4-6 weeks after start of enzalutamide]
Change in Ctrough of enzalutamide
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients with prostate cancer who will start treatment with enzalutamide within label
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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)
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Age at least 18 years
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Patients who are able and willing to give written informed consent prior to screening
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Patients from whom it is possible to collect blood samples
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Life expectancy of > 3 months
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Canisius Wilhelmina Ziekenhuis | Nijmegen | Netherlands | ||
| 2 | Radboudumc | Nijmegen | Netherlands | ||
| 3 | Franciscus Gasthuis en Vlietland hospital | Rotterdam | Netherlands |
Sponsors and Collaborators
- Radboud University Medical Center
- Astellas Pharma Inc
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MIND THE GAP