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

Drug-drug Interaction Clinical Trial

— MIND THE GAP  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05339672
• Other study ID #: MIND THE GAP
• Status: Recruiting
• Start date: July 1, 2024
• Est. completion date: August 31, 2024

Study information

• Verified date: April 2022
• Source: Radboud University Medical Center
• Contact: Emmy Boerrigter, PharmD
• Phone: +31631026328
• Email: emmy.boerrigter[@]radboudumc.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 26
• Est. completion date: August 31, 2024
• Est. primary completion date: August 31, 2024
• Gender: Male
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Drug-drug Interaction

Intervention

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)

Locations

Country	Name	City	State
Netherlands	Canisius Wilhelmina Ziekenhuis	Nijmegen
Netherlands	Radboudumc	Nijmegen
Netherlands	Franciscus Gasthuis en Vlietland hospital	Rotterdam

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University Medical Center	Astellas Pharma Inc

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the change in morphine and morphine-6-glucuronide exposure	Change in AUC0-12hr	4-6 weeks after start of enzalutamide
Primary	To determine the change in edoxaban and M4 exposure	Change in AUC0-24hr	4-6 weeks after start of enzalutamide
Secondary	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
Secondary	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
Secondary	To evaluate the effect of edoxaban and/or morphine on enzalutamide exposure	Change in Ctrough of enzalutamide	4-6 weeks after start of enzalutamide