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

NCT01911728 | Completed Phase 1

• 2 other identifiers: 9785-CL-00072011-000163-26
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 2

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).

Conditions

Pharmacokinetics of MDV3100; Castration Resistant Prostate Cancer (CRPC)

Keywords

Drug-Drug Interaction; Phase 1; MDV3100; Xtandi; Enzalutamide

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (2)

• 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)

• Monitoring of safety and tolerability through assessment of vital signs, Electrocardiogram (ECG) and clinical safety laboratory and, adverse events

  Day 1 through Day 97

Study Arms (1)

Multiple doses of MDV3100

EXPERIMENTAL

Multiple doses of MDV3100 and a single dose of pioglitazone and a single dose of cocktail containing -warfarin, omeprazole and midazolam

Drug: MDV3100; Drug: Pioglitazone; Drug: Warfarin; Drug: Omeprazole; Drug: Midazolam

Interventions

MDV3100 DRUG

Oral

Also known as: Xtandi, enzalutamide

Multiple doses of MDV3100

Pioglitazone DRUG

Oral

Multiple doses of MDV3100

Warfarin DRUG

Oral

Multiple doses of MDV3100

Omeprazole DRUG

Oral

Multiple doses of MDV3100

Midazolam DRUG

Oral

Multiple doses of MDV3100

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Astellas Pharma Europe B.V.: lead
• Medivation, Inc.: collaborator

Study Sites (2)

Parexel

George, South Africa

Location

Parexel/Qdot Pharma

Port Elizabeth, South Africa

Location

Related Publications (1)

• 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.

  PMID: 25929560 DERIVED

Related Links

• Link to results on Astellas Clinical Study Results website

MeSH Terms

Interventions

enzalutamide; Pioglitazone; Warfarin; Omeprazole; Midazolam

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Pyridines; Benzimidazoles; Benzodiazepines; Benzazepines

Study Officials

• Operation Senior Research Manager

  Astellas Pharma Europe B.V.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 26, 2013
• First Posted: July 30, 2013
• Study Start: July 25, 2011
• Primary Completion: February 21, 2012
• Study Completion: February 21, 2012
• Last Updated: June 26, 2017

Record last verified: 2017-06

Locations

ZA (2)