Drug-drug Interaction Study With MDV3100 and a Cocktail of Substrates

A Phase I Open-label Study to Evaluate the Effect of Multiple Doses of MDV3100 (ASP9785) on the Pharmacokinetics of Substrates for CYP2C8, CYP2C9, CYP2C19, and CYP3A4 in Patients With Castration-resistant Prostate Cancer

A drug-drug interaction study to investigate the potential pharmacokinetic interaction between MDV3100 and a cocktail of substrates for pioglitazone (CYP2C8 substrate), S-warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate).

Study Overview

• Status: Completed
• Conditions: Castration Resistant Prostate Cancer (CRPC); Pharmacokinetics of MDV3100
• Intervention / Treatment: Drug: Midazolam; Drug: MDV3100; Drug: Warfarin; Drug: Pioglitazone; Drug: Omeprazole

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• South Africa
  • George, South Africa
    • Parexel
  • Port Elizabeth, South Africa
    • Parexel/Qdot Pharma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features;
• Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or orchiectomy (i.e., medical or surgical castration);

• Progressive disease by prostate specific antigen (PSA) or imaging whether or not after chemotherapy in the setting of medical or surgical castration. Disease progression for study entry is defined as one or more of the following 3 criteria:

  • PSA progression defined by a minimum of 3 rising PSA levels with an interval of ≥1 week between each determination. The PSA value during the pre investigational period should be ≥2 μg/L (2 ng/mL);
  • Soft tissue disease progression defined by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) for soft tissue disease (see Appendix A);
  • Bone disease progression defined by two or more new lesions on bone scan.

Exclusion Criteria:

• Confirmed CYP2C8, CYP2C9, or CYP2C19 poor metabolizer status based on genotyping analysis;
• Absolute neutrophil count < 1,500/μL, platelet count < 100,000/μL, and hemoglobin < 5.6 mmol/L (9 g/dL) during the screening period (NOTE: patients may not have received any growth factors or blood transfusions within 7 days prior to the hematologic laboratory values obtained during the screening period);
• Total bilirubin > 1.5 times, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper limit of normal during the screening period;
• Creatinine > 177 μmol/L (2 mg/dL) during the screening period;
• Albumin < 30 g/L (3.0 g/dL) during the screening period;
• Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide), 5 α reductase inhibitors (finasteride, dutasteride), estrogens, or chemotherapy within 4 weeks prior to enrollment (Day 1 visit) or plans to initiate treatment with any of these treatments during the study;
• Use of herbal products that may decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone/prednisolone per day within 4 weeks prior to enrollment (Day 1 visit) or plans to initiate treatment with any of these treatments during the study;
• Structurally unstable bone lesions suggesting impending fracture;
• History of seizure, including any febrile seizure, loss of consciousness, or transient ischemia attack within 12 months prior to enrollment (Day 1 visit), or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Multiple doses of MDV3100; Multiple doses of MDV3100 and a single dose of pioglitazone and a single dose of cocktail containing -warfarin, omeprazole and midazolam	Drug: Midazolam; Oral; Drug: MDV3100; Oral; Other Names: Xtandi; enzalutamide; Drug: Warfarin; Oral; Drug: Pioglitazone; Oral; Drug: Omeprazole; Oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the pharmacokinetic profile of pioglitazone (CYP2C8 substrate) in combination with MDV3100 PTM and MDV3100	(Maximum concentration (observed))Cmax, (Area Under Curve from the time of dosing to the last measurable concentration)AUC0-t, (AUC extrapolated to infinity)AUC0-inf	Day 1 through Day 72 (75 times)
Assessment of the pharmacokinetic profile of S-warfarin (CYP2C9 substrate) in combination with MDV3100 PTM and MDV3100	(Maximum concentration (observed))Cmax, (Area Under Curve from the time of dosing to the last measurable concentration)AUC0-t, (AUC extrapolated to infinity)AUC0-inf	Day 1 through Day 72 (75 times)
Assessment of the pharmacokinetic profile of omeprazole (CYP2C19 substrate) in combination with MDV3100 PTM and MDV3100	(Maximum concentration (observed))Cmax, (Area Under Curve from the time of dosing to the last measurable concentration)AUC0-t, (AUC extrapolated to infinity)AUC0-inf	Day 1 through Day 72 (75 times)
Assessment of the pharmacokinetic profile of midazolam (CYP3A4 substrate) in combination with MDV3100 PTM and MDV3100	(Maximum concentration (observed))Cmax, (Area Under Curve from the time of dosing to the last measurable concentration)AUC0-t, (AUC extrapolated to infinity)AUC0-inf	Day 1 through Day 72 (75 times)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the pharmacokinetic profile of substrates pioglitazone (CYP2C8 substrate), S-warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) in combination with MDV3100 PTM and MDV3100	(Time to attain Cmax)tmax (Apparent terminal elimination half-life)t1/2, (Apparent total body clearance after extravascular dosing)CL/F, (Apparent volume of distribution during the terminal phase after extravascular dosing)Vz/F, Cmax, AUC0-t, AUC0-inf, (Pre-dose plasma concentration)C0h, (Minimum concentration (observed))Cmin, (AUC between two consecutive doses at steady-state)AUCtau, (Peak-trough ratio)PTR	Day 1 through Day 72 (75 times)
Monitoring of safety and tolerability through assessment of vital signs, Electrocardiogram (ECG) and clinical safety laboratory and, adverse events		Day 1 through Day 97

Collaborators and Investigators

• Sponsor: Astellas Pharma Europe B.V.
• Collaborators: Medivation, Inc.

Publications and helpful links

General Publications

• Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, Mol R, Mordenti J, Ouatas T. Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet. 2015 Oct;54(10):1057-69. doi: 10.1007/s40262-015-0283-1.

Helpful Links

• Link to results on Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2011
• Primary Completion (Actual): February 21, 2012
• Study Completion (Actual): February 21, 2012

Study Registration Dates

• First Submitted: July 26, 2013
• First Submitted That Met QC Criteria: July 26, 2013
• First Posted (Estimate): July 30, 2013

Study Record Updates

• Last Update Posted (Actual): June 26, 2017
• Last Update Submitted That Met QC Criteria: June 22, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Phase 1; Xtandi; MDV3100; Enzalutamide; Drug-Drug Interaction
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticoagulants; Anti-Ulcer Agents; Proton Pump Inhibitors; Midazolam; Pioglitazone; Warfarin; Omeprazole
• Other Study ID Numbers: 9785-CL-0007; 2011-000163-26 (EudraCT Number)