Drug-drug-interaction Study to Assess the Effect of Darolutamide on the Pharmacokinetics of Probe Substrates of CYP3A4 and P-gp in Healthy Male Volunteers

NCT03237416 | Completed Phase 1

• 2 other identifiers: 188602017-001116-11
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

Evaluate the effect of darolutamide on the pharmacokinetics of a probe CYP3A4 substrate and Pgp substrate

Conditions

Prostatic Neoplasms

Keywords

Drug-drug interaction

Outcome Measures

Primary Outcomes (4)

• AUC in plasma of non-conjugated dabigatran (AUC(0-tlast), if AUC cannot be calculated)

  Exposure of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate AUC: area under the concentration vs. time curve from zero to infinity after single (first) dose AUC(0-tlast): AUC from time 0 to the last data point \> LLOQ

  Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

• C(max) in plasma of non-conjugated dabigatran

  Maximum plasma concentration of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate Cmax: maximum observed drug concentration in measured matrix after single dose administration

  Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

• AUC in plasma of midazolam (AUC(0-tlast), if AUC cannot be calculated)

  Exposure of midazolam in plasma following a single administration of midazolam

  PPeriod 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

• C(max) in plasma of midazolam

  Maximum plasma concentration of midazolam in plasma following a single administration of midazolam

  Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

Secondary Outcomes (5)

• Number of subjects with study drug-related treatment-emergent Adverse Event (TEAE)

  30 days following last intake of Investigational Product

• AUC in plasma of total dabigatran (AUC(0-tlast), if AUC cannot be calculated)

  Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

• C(max) in plasma of total dabigatran

  Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

• AUC in plasma of 1-OH midazolam (AUC(0-tlast), if AUC cannot be calculated)

  Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

• C(max) in plasma of 1-OH midazolam

  PPeriod 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

Study Arms (1)

BAY1841788/Healthy subjects

EXPERIMENTAL

Period 1: intake of Midazolam and Dabigatran etexilate at day 1 followed by Period 2: intake of Darolutamide at days 1-11 (twice daily), intake of dabigatran etexilate at days 3 and 9, intake of Midazolam at day 9

Drug: Dabigatran etexilate; Drug: Midazolam; Drug: BAY1841788 (darolutamide)

Interventions

Dabigatran etexilate DRUG

In Period 1, Day 1 a single dose of 75 mg will be administered after breakfast In Period 2, Day 3 a single dose of 75 mg will be administered prior to breakfast In Period 2, Day 9 a single dose of 75 mg will be administered after breakfast

BAY1841788/Healthy subjects

Midazolam DRUG

In Period 1, Day 1 a single dose of 1 mg will be administered after breakfast In Period 2, Day 9 a single dose of 1 mg will be administered after breakfast

BAY1841788/Healthy subjects

BAY1841788 (darolutamide) DRUG

In Period 2, Days 1-11 600 mg twice a day (as 2 x 300 mg tablets) will be administered after breakfast

BAY1841788/Healthy subjects

Eligibility Criteria

• Age: 45 Years - 65 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy subject - as determined by the investigator or medically qualified designee based on medical evaluations including medical history, physical examination, laboratory tests and cardiac monitoring.
• Gender: Male.
• Age: 45 to 65 years (inclusive) at the screening visit.
• Race: White.
• Body mass index (BMI): ≥18.0 and ≤30.0 kg/m2.
• Agree to use condoms as an effective contraception barrier method and refrain from sperm donation during the whole study (starting after informed consent) and for 3 months after the end of treatment with darolutamide.
• In addition, participants must agree to utilize a second reliable method of contraception simultaneously. The second method which has to be used by a female partner of childbearing potential can be one of the following methods: diaphragm or cervical cap with spermicide or intra-uterine device or hormone-based contraception. Therefore, contraception methods to be used by male subjects and female partners are in line with clinical trial facilitation group recommendations related to contraception in clinical trials.
• Ability to understand and follow study-related instructions.
• Results of alcohol tests are negative at screening and on Study Day -1.
• Confirmation of the subject's health insurance coverage prior to the first screening examination/visit.

You may not qualify if:

• Existing relevant diseases of vital organs (e.g. liver diseases, heart diseases), central nervous system (for example seizures) or other organs (e.g. diabetes mellitus).
• Incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, elimination and effects of the study drugs will not be normal.
• Known history of hypersensitivity (or known allergic reaction) to medications including any ingredient of midazolam, benzodiazepines, dabigatran etexilate, or darolutamide.
• Relevant hepatic disorders like cholestasis, disturbances of bilirubin metabolism, any progressive liver disease.
• Relevant renal disorders like recurrent glomerulonephritis, renal injury, and renal insufficiency. However, a history of a single episode of uncomplicated nephrolithiasis will not prevent participation.
• CYP3A4 inhibitors within 1 week or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
• CYP3A4 inducers as well as St John's Wort within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
• Known BCRP and OATP substrates within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
• P-gp inducers (e.g. rifampin) within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
• P-gp inhibitors within 1 week or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.

Sponsors & Collaborators

• Bayer: lead
• Orion Corporation, Orion Pharma: collaborator

Study Sites (1)

CRS Clinical-Research-Services Mannheim GmbH

Mannheim, Baden-Wurttemberg, 68167, Germany

Location

Related Links

• Click here to find results for studies related to Bayer Healthcare products.

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Dabigatran; Midazolam; darolutamide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzodiazepines; Benzazepines

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 26, 2017
• First Posted: August 2, 2017
• Study Start: August 2, 2017
• Primary Completion: October 5, 2017
• Study Completion: December 18, 2017
• Last Updated: November 6, 2018

Record last verified: 2018-11

Locations

DE (1)