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

Phase 1

Completed

• Conditions: Castration Resistant Prostate Cancer (CRPC); Pharmacokinetics of MDV3100
• Interventions: Drug: MDV3100; Drug: Pioglitazone; Drug: Warfarin; Drug: Omeprazole; Drug: Midazolam

• Registration Number: NCT01911728
• Lead Sponsor: Astellas Pharma Europe B.V.

Brief Summary

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).

Detailed Description

Not available

Study Timeline

• Study Start: 2011-07-25
• Primary Completion: 2012-02-21
• Study Completion: 2012-02-21
• Study First Submitted: 2013-07-26
• Study First Submitted QC: 2013-07-26
• Study First Posted: 2013-07-30
• Status Verified: 2017-06
• Last Update Submitted: 2017-06-22
• Last Update Posted: 2017-06-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 14

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Multiple doses of MDV3100	MDV3100	Multiple doses of MDV3100 and a single dose of pioglitazone and a single dose of cocktail containing -warfarin, omeprazole and midazolam
Multiple doses of MDV3100	Midazolam	Multiple doses of MDV3100 and a single dose of pioglitazone and a single dose of cocktail containing -warfarin, omeprazole and midazolam
Multiple doses of MDV3100	Warfarin	Multiple doses of MDV3100 and a single dose of pioglitazone and a single dose of cocktail containing -warfarin, omeprazole and midazolam
Multiple doses of MDV3100	Omeprazole	Multiple doses of MDV3100 and a single dose of pioglitazone and a single dose of cocktail containing -warfarin, omeprazole and midazolam
Multiple doses of MDV3100	Pioglitazone	Multiple doses of MDV3100 and a single dose of pioglitazone and a single dose of cocktail containing -warfarin, omeprazole and midazolam

Primary Outcome Measures

Name	Time	Method
Assessment of the pharmacokinetic profile of pioglitazone (CYP2C8 substrate) in combination with MDV3100 PTM and MDV3100	Day 1 through Day 72 (75 times)	(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
Assessment of the pharmacokinetic profile of S-warfarin (CYP2C9 substrate) in combination with MDV3100 PTM and MDV3100	Day 1 through Day 72 (75 times)	(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
Assessment of the pharmacokinetic profile of omeprazole (CYP2C19 substrate) in combination with MDV3100 PTM and MDV3100	Day 1 through Day 72 (75 times)	(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
Assessment of the pharmacokinetic profile of midazolam (CYP3A4 substrate) in combination with MDV3100 PTM and MDV3100	Day 1 through Day 72 (75 times)	(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

Secondary Outcome Measures

Name	Time	Method
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	Day 1 through Day 72 (75 times)	(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
Monitoring of safety and tolerability through assessment of vital signs, Electrocardiogram (ECG) and clinical safety laboratory and, adverse events	Day 1 through Day 97

Trial Locations

Locations (2)

Parexel; 🇿🇦 George, South Africa

Parexel/Qdot Pharma; 🇿🇦 Port Elizabeth, South Africa