Evaluation of Enzalutamide's Impact on Edoxaban and Morphine Pharmacokinetics in Prostate Cancer Patients

The primary objective of this study is to determine the change in exposure of **edoxaban** and its metabolite M4 (AUC0-24hr) with or without the presence of **enzalutamide**. Additionally, the study aims to assess the change in exposure of **morphine** and its metabolite morphine-6-glucuronide (AUC0-12hr) with or without enzalutamide. These evaluations are clinically relevant as they aim to elucidate potential drug-drug interactions that could impact the pharmacological management of patients with prostate cancer, ensuring more effective and safer treatment regimens.

Secondary objectives include evaluating pain control using the Numeric Rating Scale in patients treated with and without enzalutamide and morphine, assessing the safety of combining enzalutamide with edoxaban and/or morphine using CTC-AE v 5.0 criteria, and determining the effect of edoxaban and/or morphine on enzalutamide exposure. These objectives are crucial for understanding the broader implications of these drug interactions on patient safety and treatment efficacy.

The clinical trial involves **male** participants diagnosed with **prostate cancer**. The study population is composed of individuals aged 18 years and older, with a life expectancy of more than three months and stable renal function, indicated by a renal clearance greater than 50 ml/min. Participants are required to be on treatment with either enzalutamide, edoxaban, or morphine, with specific conditions for switching between immediate-release and extended-release formulations of morphine. The trial does not include a vulnerable population, and all participants must be able and willing to provide written informed consent. The sponsor has not provided information regarding the total number of participants in the study. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **interaction** between **enzalutamide**, **morphine**, and **edoxaban** in patients with **prostate cancer**. This is a Phase IV, low-intervention study, characterized by a randomized, double-blind, controlled design. The trial aims to determine the change in exposure levels of edoxaban and its metabolite M4, as well as morphine and morphine-6-glucuronide, with or without the administration of enzalutamide. The study is expected to run from October 2022 to December 2025, with participant involvement lasting up to 1000 days, depending on individual treatment regimens.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, renal function, and current treatment status. Eligible participants will be those with prostate cancer who are either starting or currently on enzalutamide treatment, and who are also receiving or willing to switch to specific doses of edoxaban or morphine. Follow-up visits will be scheduled to monitor drug exposure levels, safety, and efficacy, using the Numeric Rating Scale for pain control and CTC-AE v 5.0 criteria for safety assessment. The end-of-study visit will conclude the trial, where final assessments and data collection will occur.

Participants may be withdrawn from the study if they experience adverse effects that compromise safety, fail to comply with the study protocol, or if their condition changes such that continued participation is deemed inappropriate. The primary endpoints focus on pharmacokinetic changes, while secondary endpoints include evaluating pain control and the safety of drug combinations. The trial's design ensures that all procedures align with standard treatment protocols, minimizing additional risks to participants.

The clinical trial involves the administration of three **experimental medications**: **Morphine**, **Edoxaban**, and **Enzalutamide**. **Morphine** is administered in an oral pharmaceutical form, identified by the code PHF00231MIG. The maximum daily dose is 400 mg, with a total maximum dose of 400 mg over a treatment period of up to 1000 days. The administration route is oral, and the medication is not a pediatric formulation. **Morphine** is classified under the ATC code N02AA01, indicating its role as an opioid analgesic.

**Edoxaban** is also administered orally, with a pharmaceutical form code of PHF00082MIG. The maximum daily dose is 60 mg, with a total maximum dose of 60 mg over a treatment period of up to 1000 days. **Edoxaban** is a direct oral anticoagulant (DOAC) and is classified under the ATC code B01AF03. The active substance is of chemical origin, and the medication is not formulated for pediatric use.

**Enzalutamide** is administered in an oral form, identified by the pharmaceutical form code PHF00007MIG. The maximum daily dose is 160 mg, with a total maximum dose of 160 mg over a treatment period of up to 1000 days. **Enzalutamide** is an oral oncolytic agent, classified under the ATC code L02BB04. The active substance is chemically derived, and the formulation is not intended for pediatric use.

Throughout the trial, participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed regimen. The trial aims to evaluate the pharmacokinetic interactions between **Enzalutamide** and the other two medications, **Morphine** and **Edoxaban**, to optimize pharmacological care for patients with prostate cancer. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study.

Efficacy in this clinical trial will be assessed by evaluating the pharmacokinetic interactions between **enzalutamide** and the drugs **edoxaban** and **morphine** in patients with prostate cancer. The primary endpoints include determining the change in edoxaban and its metabolite M4 exposure (AUC0-24hr) and the change in morphine and morphine-6-glucuronide exposure (AUC0-12hr) with or without enzalutamide. These measurements will be conducted using validated pharmacokinetic methods to assess the area under the concentration-time curve (AUC) at specified intervals.

Secondary endpoints will focus on evaluating pain control in patients treated with and without enzalutamide and morphine, using the Numeric Rating Scale. Additionally, the safety of the combination of enzalutamide with edoxaban and/or morphine will be monitored according to the Common Terminology Criteria for Adverse Events (CTC-AE) version 5.0. The effect of edoxaban and/or morphine on enzalutamide exposure will also be assessed. These assessments will provide comprehensive data on the efficacy and safety of the drug interactions in the specified patient population.