Prostatic Neoplasms
Conditions
Keywords
Drug-drug interaction
Brief summary
Evaluate the effect of darolutamide on the pharmacokinetics of a probe CYP3A4 substrate and Pgp substrate
Interventions
DRUGDabigatran 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
DRUGMidazolam
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
DRUGBAY1841788 (darolutamide)
In Period 2, Days 1-11 600 mg twice a day (as 2 x 300 mg tablets) will be administered after breakfast
Sponsors
Orion Corporation, Orion Pharma
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
45 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC in plasma of non-conjugated 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 | 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 |
| C(max) in plasma of non-conjugated 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 | 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 |
| AUC in plasma of midazolam (AUC(0-tlast), if AUC cannot be calculated) | 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 | Exposure of midazolam in plasma following a single administration of midazolam |
| C(max) in plasma 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 | Maximum plasma concentration of midazolam in plasma following a single administration of midazolam |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects with study drug-related treatment-emergent Adverse Event (TEAE) | 30 days following last intake of Investigational Product | — |
| 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 | Maximum plasma concentration of 1-OH midazolam in plasma following a single administration of midazolam |
| 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 | Exposure of total dabigatran in plasma following a single administration of dabigatran etexilate |
| 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 | Maximum plasma concentration of total dabigatran in plasma following a single administration of dabigatran etexilate |
| 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 | Exposure of 1-OH midazolam in plasma following a single administration of midazolam |
Countries
Germany
Outcome results
None listed