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

Radboud University Medical Center

Status: Enrolling

Conditions: Drug-drug Interaction

Treatments: Other: Blood sampling - Pharmacokinetic assessment

Study type: Observational

Funder types: Other; Industry

Identifiers

NCT05339672

MIND THE GAP

Details and patient eligibility

About

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.

Enrollment: 26 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

26 participants in 2 patient groups

Morphine

Description:

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

Treatment:

Other: Blood sampling - Pharmacokinetic assessment

Edoxaban

Description:

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

Treatment:

Other: Blood sampling - Pharmacokinetic assessment