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

A Phase I, Non-randomized, Open-label, Fixed-sequence Study to Investigate the Effect of Darolutamide (ODM-201) on the Pharmacokinetics of a Probe Substrate of CYP3A4 and P-gp in Healthy Male Volunteers

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

Study Overview

• Status: Completed
• Conditions: Prostatic Neoplasms
• Intervention / Treatment: Drug: Dabigatran etexilate; Drug: Midazolam; Drug: BAY1841788 (darolutamide)

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Mannheim, Baden-Württemberg, Germany, 68167
      • CRS Clinical-Research-Services Mannheim GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: BAY1841788/Healthy subjects; 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; 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; Drug: Midazolam; 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; Drug: BAY1841788 (darolutamide); In Period 2, Days 1-11 600 mg twice a day (as 2 x 300 mg tablets) will be administered after breakfast

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Exposure of total dabigatran in plasma following a single administration of dabigatran etexilate	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	Maximum plasma concentration of total dabigatran in plasma following a single administration of dabigatran etexilate	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)	Exposure of 1-OH 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
C(max) in plasma of 1-OH midazolam	Maximum plasma concentration of 1-OH 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

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Orion Corporation, Orion Pharma

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2017
• Primary Completion (Actual): October 5, 2017
• Study Completion (Actual): December 18, 2017

Study Registration Dates

• First Submitted: July 26, 2017
• First Submitted That Met QC Criteria: July 31, 2017
• First Posted (Actual): August 2, 2017

Study Record Updates

• Last Update Posted (Actual): November 6, 2018
• Last Update Submitted That Met QC Criteria: November 5, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Drug-drug interaction
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Protease Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Midazolam; Dabigatran
• Other Study ID Numbers: 18860; 2017-001116-11 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No