Determining the Clinical Relevance of the Interaction Between Enzalutamide and the Opioid Morphine and the DOAC Edoxaban (MIND THE GAP)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Drug-drug Interaction
• Intervention / Treatment: Other: Blood sampling - Pharmacokinetic assessment

• Study Type: Observational
• Enrollment (Anticipated): 26

Contacts and Locations

• Study Contact: Name: Emmy Boerrigter, PharmD; Phone Number: +31631026328; Email: emmy.boerrigter@radboudumc.nl
• Study Contact Backup: Name: Nielka van Erp, PharmD, PhD; Phone Number: +31611417813; Email: nielka.vanerp@radboudumc.nl

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • Recruiting
    • Radboudumc
    • Contact: Nielka van Erp, Dr.
    • Sub-Investigator: Inge van Oort, Dr.
    • Sub-Investigator: Niven Mehra, Dr.
  • Nijmegen, Netherlands
    • Not yet recruiting
    • Canisius Wilhelmina Ziekenhuis
    • Contact: Rik Somford, MD,PhD
    • Sub-Investigator: Rik Somford, MD, PhD
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Franciscus Gasthuis en Vlietland hospital
    • Contact: Paul Hamberg, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

Patients with prostate cancer starting enzalutamide therapy

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Crossover
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	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)

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Astellas Pharma Inc

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2024
• Primary Completion (Anticipated): August 31, 2024
• Study Completion (Anticipated): August 31, 2024

Study Registration Dates

• First Submitted: April 14, 2022
• First Submitted That Met QC Criteria: April 14, 2022
• First Posted (Actual): April 21, 2022

Study Record Updates

• Last Update Posted (Actual): October 27, 2022
• Last Update Submitted That Met QC Criteria: October 26, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: Mind The Gap

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No