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

NCT05339672 | Unknown

• 1 other identifier: MIND THE GAP
• Study Type: observational
• Target: 26
• Locations: 1 country
• Sites: 3

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.

Conditions

Drug-drug Interaction

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• To evaluate the pain control in patients treated with and without enzalutamide and morphine

  4-6 weeks after start of enzalutamide

• To evaluate the safety of the combination of enzalutamide with edoxaban and/or morphine

  4-6 weeks after start of enzalutamide

• To evaluate the effect of edoxaban and/or morphine on enzalutamide exposure

  4-6 weeks after start of enzalutamide

Study Arms (2)

Morphine

The participating patients are treated with morphine before start of enzalutamide (according to label).

Other: Blood sampling - Pharmacokinetic assessment

Edoxaban

The participating patients are treated with edoxaban before start of enzalutamide (according to label).

Other: Blood sampling - Pharmacokinetic assessment

Interventions

Blood sampling - Pharmacokinetic assessment OTHER

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; Morphine

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with prostate cancer starting enzalutamide therapy

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Astellas Pharma Inc: collaborator

Study Sites (3)

Canisius Wilhelmina Ziekenhuis

Nijmegen, Netherlands

NOT YET RECRUITING

Radboudumc

Nijmegen, Netherlands

RECRUITING

Franciscus Gasthuis en Vlietland hospital

Rotterdam, Netherlands

NOT YET RECRUITING

Central Study Contacts

Emmy Boerrigter, PharmD

CONTACT

+31631026328; emmy.boerrigter@radboudumc.nl

Nielka van Erp, PharmD, PhD

CONTACT

+31611417813; nielka.vanerp@radboudumc.nl

Study Design

• Study Type: observational
• Observational Model: CASE CROSSOVER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2022
• First Posted: April 21, 2022
• Study Start: July 1, 2024
• Primary Completion: August 31, 2024
• Study Completion: August 31, 2024
• Last Updated: October 27, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

NL (3)