Determining the Effect of Abiraterone on the Metabolism of Oxycodone in Men With Prostate Cancer (the ENABLE Study)

Rationale: Oxycodone is an opioid receptor agonist metabolized primarily by CYP3A4, and to a lesser extent by CYP2D6. Abiraterone is an androgen biosynthesis inhibitor prescribed to men with castration resistant prostate cancer (CRPC). The ENABLE study is a follow-up to the ENZYME study in which it was described that enzalutamide increases oxycodone metabolism in patients with CRPC. It is expected that concomitant use of abiraterone has no clinically relevant effect on oxycodone's plasma concentration since it solely inhibits CYP2D6. Therefore, discontinuing abiraterone treatment is not expected to result in toxicity. This might positively affect pain management and pharmacovigilance in patients with CRPC.

Objective: To investigate the effect of abiraterone on the pharmacokinetics (PK) of oxycodone following a single dose of 15 mg normal-release oxycodone in men with prostate cancer.

Trial design: A prospective, open-label, two-arm parallel clinical study.

Subjects will visit the hospital once for approximately nine hours. After screening for hypercapnia, subjects will receive one oral dose of 15 mg (10 mg and 5 mg capsules) normal-release oxycodone. In total, nine blood samples will be collected during the day for the control group and ten blood samples for the abiraterone group. Seven blood samples will be collected at predetermined times (t= 0.5, 1, 1.5, 2, 3, 5, 8 hours) in order to analyze the metabolism of oxycodone. One blood sample will be collected to determine abiraterone serum trough concentrations (abiraterone arm). In addition, two blood samples will be collected for patient characteristics, including one sample for genotyping of CYP3A4 and CYP2D6.

Inclusion criteria

• Diagnosed prostate cancer;
• Males aged 18 years or older;
• Treated with abiraterone 1000 mg once daily for at least 10 days (abiraterone arm).
• Not treated with abiraterone 1000 mg once daily for at least 10 days (control arm).

Exclusion criteria

• Use of oxycodone short acting <48 hours, or long acting <96 hours prior to the study day;
• Use of other opioids in the 14 days prior to the study day (see also appendix A);
• Use of other medication that has pharmacokinetic or pharmacodynamics interactions with oxycodone (see also appendix A);
• Arm 1: dose reduction or successive days of treatment interruption within 10 days prior to the study day (arm 1);
• Arm 2: treatment with abiraterone within 10 days prior to the study day;
• A body mass index (BMI) outside the range of 18 - 30 kg/m2;
• If hypersensitive to oxycodone;
• patients suffering from diarrhea
• If any type of abnormality; active or symptomatic viral hepatitis or chronic liver disease (e.g. classification with Child-Pugh B, Child-Pugh C);
• Known metastases in the liver that would affect drug metabolism;
• Patients with a CYP3A4 or CYP2D6 polymorphism;
• Moderate-severe renal dysfunction (GFR <60 ml/min/1.73m2) that affects drug metabolism ;
• Subjects with significant respiratory depression resulting in the need of oxygen therapy or objective hypoventilation (respiratory rate <12/min);
• Hypercapnia (venous pCO2 outside the range of 5.5 - 6.7; pH outside the range 7.30 - 7.40);
• Subjects with, a history of bronchial asthma, chronic obstructive pulmonary disease or pulmonary heart disease;
• Subjects who started their first cycle of chemotherapy during the 2 weeks before the study day;
• Major surgery within 1 month prior to screening or planned surgery;
• A history of drug abuse
• Patients receiving opioid substitution therapy for opioid addiction (e.g. methadone or buprenorphine) and/or suffering from opioid withdrawal
• Patients with evidence of clinically significant gastrointestinal disease;
• Patients who are contraindicated for blood sampling;
• Unable to swallow solid, oral dosage forms whole with water;
• Participation in a clinical trial study at the time of enrolment or within 30 days or 5 half-lives of enrolment, whichever is longer;
• Previous gastric bypass or gastric band surgery.