Healthy
Conditions
Brief summary
The objective of the current study is to evaluate the effect of once daily itraconazole on the pharmacokinetics of BI 409306 in poor (PM) and extensive metabolisers (EM) of CYP2C19.
Interventions
DRUGBI 409306
Oral single dose of BI 409306
DRUGItraconazole
Oral dose, twice daily on Day -3, once daily on Day -2 to Day 2 of Itraconazole
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
\- Healthy CYP2C19 genotyped male volunteers according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR, respiratory rate, body temperature), 12-lead ECG, ophthalmologic exam, clinical laboratory tests * Korean ethnicity according to the following criteria: be a current Korean passport or national identification card holder, and have parents and grandparents who were all born in Korea * Age 20 or older than 20 and 45 or younger than 45 years * BMI (Body Mass Index) 18.5 or more than 18.5 and BMI 25 or less than 25 kg/m2 * Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation.
Exclusion criteria
* Any finding of the medical examination (including BP, PR, respiratory rate, body temperature and ECG) deviating from normal and of clinical relevance * Any evidence of a clinically relevant concomitant disease * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Surgery of the gastrointestinal tract (except appendectomy, hernia surgery) * Diseases of the central nervous system (including but not limited to any kind of seizures, migraine, stroke or psychiatric disorders) within the past 6 month * History of relevant orthostatic hypotension, fainting spells or blackouts. * Chronic or relevant acute infections * History of relevant allergy/hypersensitivity (including allergy to drug or its excipients) * Intake of drugs with a long half-life (longer than 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial * Use of drugs which might reasonably influence the results of the trial or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial * Participation in another trial with an investigational drug within two months prior to administration or during the trial * Smoker (more than 10 cigarettes or more than 3 cigars or more than 3 pipes/day) * Inability to refrain from smoking on trial days * Alcohol abuse (more than 20 g/day) * Drug abuse * Blood donation (more than 100 mL within four weeks prior to administration or during the trial) * Excessive physical activities (within one week prior to administration or during the trial) * Any laboratory value outside the reference range that is of clinical relevance * Inability to comply with dietary regimen of trial site * A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval more than 450 ms) * A history of additional risk factors for Torsade des Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) * Abnormality on color vision test or any other finding on ophthalmologic exam that is clinically deemed to potentially interfere with the safety assessment of this trial * Subjects who do not agree to minimize the risk of female partners becoming pregnant from the first dosing day until two month after the study completion. Acceptable methods of contraception comprises barrier contraception and a medically accepted contraceptive method for the female partner (intra-uterine device with spermicide, hormonal contraceptive since at least two month)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-infinity of BI 409306 and Its Metabolites | 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity) of BI 409306 and its metabolites CD 13896 and CD 14084 |
| Cmax of BI 409306 and Its Metabolites | 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration | Maximum measured concentration of the analyte in plasma (Cmax) of BI 409306 and its metabolites CD 13896 and CD 14084 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz of BI 409306 and Its Metabolites | 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable plasma concentration (AUC0-tz) of BI 409306 and its metabolites CD 13896 and CD 14084 |
| Tmax of BI 409306 and Its Metabolites | 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration | Time from dosing to the maximum concentration of the analyte in plasma (tmax) of BI 409306 and its metabolites CD 13896 and CD 14084 |
| t1/2 of BI 409306 and Its Metabolites | 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration | Terminal half-life of the analyte in plasma (t1/2) of BI 409306 and its metabolites CD 13896 and CD 14084 |
Countries
South Korea
Participant flow
Recruitment details
A randomised, open-label, 2-way crossover trial. The two treatment periods were separated by a washout period of at least 3 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Extensive Metabolisers Participants who were extensive metabolisers received two treatments in a randomised order, the treatments were:
* Reference (ref) treatment (1 single tablet of 25 mg BI 409306 taken orally on day 1).
* Test treatment (2 capsules of 100 mg itraconazole taken orally twice daily on day -3 (loading dose) and once daily on day -2 to day 2, plus 1 tablet of 25 mg BI 409306 taken orally as a single dose 1 hour after the itraconazole administration on day 1. | 13 |
| Poor Metabolisers Participants who were poor metabolisers received two treatments in a randomised order, the treatments were:
* Reference (ref) treatment (1 single tablet of 25 mg BI 409306 taken orally on day 1).
* Test treatment (2 capsules of 100 mg itraconazole taken orally twice daily on day -3 (loading dose) and once daily on day -2 to day 2, plus 1 tablet of 25 mg BI 409306 taken orally as a single dose 1 hour after the itraconazole administration on day 1. | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 | Adverse Event | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Extensive Metabolisers | Poor Metabolisers | Total |
|---|---|---|---|
| Age, Continuous | 32.2 Years STANDARD_DEVIATION 8.36 | 29.7 Years STANDARD_DEVIATION 6.53 | 31.0 Years STANDARD_DEVIATION 7.49 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 13 | 1 / 12 | 3 / 12 | 1 / 12 | 3 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
AUC0-infinity of BI 409306 and Its Metabolites
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity) of BI 409306 and its metabolites CD 13896 and CD 14084
Time frame: 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration
Population: Pharmacokinetic set (PKS) which included all treated subjects who provided at least one evaluable primary or secondary endpoint in any of the study periods without important protocol violations with respect to the statistical evaluation of relative bioavailability.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Extensive Metabolisers: Ref. Treatment | AUC0-infinity of BI 409306 and Its Metabolites | BI 409306 | 547 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 71.6 |
| Extensive Metabolisers: Ref. Treatment | AUC0-infinity of BI 409306 and Its Metabolites | CD 14084 | 2120 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 10.9 |
| Extensive Metabolisers: Ref. Treatment | AUC0-infinity of BI 409306 and Its Metabolites | CD 13896 | 389 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 26.4 |
| Extensive Metabolisers: Test Treatment | AUC0-infinity of BI 409306 and Its Metabolites | BI 409306 | 621 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 68.8 |
| Extensive Metabolisers: Test Treatment | AUC0-infinity of BI 409306 and Its Metabolites | CD 14084 | 2110 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 12.6 |
| Extensive Metabolisers: Test Treatment | AUC0-infinity of BI 409306 and Its Metabolites | CD 13896 | 347 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 19.2 |
| Poor Metabolisers: Ref. Treatment | AUC0-infinity of BI 409306 and Its Metabolites | CD 13896 | 178 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 20 |
| Poor Metabolisers: Ref. Treatment | AUC0-infinity of BI 409306 and Its Metabolites | BI 409306 | 1560 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 45.5 |
| Poor Metabolisers: Ref. Treatment | AUC0-infinity of BI 409306 and Its Metabolites | CD 14084 | 1810 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 15.7 |
| Poor Metabolisers: Test Treatment | AUC0-infinity of BI 409306 and Its Metabolites | BI 409306 | 1370 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 39.4 |
| Poor Metabolisers: Test Treatment | AUC0-infinity of BI 409306 and Its Metabolites | CD 14084 | 1890 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 14.2 |
| Poor Metabolisers: Test Treatment | AUC0-infinity of BI 409306 and Its Metabolites | CD 13896 | 165 nanomole (nmol)*hour (h) /Liter (L) | Geometric Coefficient of Variation 14.3 |
Comparison: Analysis for BI 40930690% CI: [100.522, 128.376]
Comparison: Analysis for BI 40930690% CI: [77.839, 99.452]
Comparison: Analysis for CD 1389690% CI: [84.636, 94.021]
Comparison: Analysis of CD 1389690% CI: [88.592, 97.396]
Comparison: Analysis for CD 1408490% CI: [95.796, 103.584]
Comparison: Analysis for CD 1408490% CI: [98.783, 110.278]
Primary
Cmax of BI 409306 and Its Metabolites
Maximum measured concentration of the analyte in plasma (Cmax) of BI 409306 and its metabolites CD 13896 and CD 14084
Time frame: 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Extensive Metabolisers: Ref. Treatment | Cmax of BI 409306 and Its Metabolites | BI 409306 | 264 nmol/L | Geometric Coefficient of Variation 67.8 |
| Extensive Metabolisers: Ref. Treatment | Cmax of BI 409306 and Its Metabolites | CD 14084 | 714 nmol/L | Geometric Coefficient of Variation 21.5 |
| Extensive Metabolisers: Ref. Treatment | Cmax of BI 409306 and Its Metabolites | CD 13896 | 139 nmol/L | Geometric Coefficient of Variation 41.6 |
| Extensive Metabolisers: Test Treatment | Cmax of BI 409306 and Its Metabolites | BI 409306 | 246 nmol/L | Geometric Coefficient of Variation 60.2 |
| Extensive Metabolisers: Test Treatment | Cmax of BI 409306 and Its Metabolites | CD 14084 | 620 nmol/L | Geometric Coefficient of Variation 19.1 |
| Extensive Metabolisers: Test Treatment | Cmax of BI 409306 and Its Metabolites | CD 13896 | 110 nmol/L | Geometric Coefficient of Variation 35.5 |
| Poor Metabolisers: Ref. Treatment | Cmax of BI 409306 and Its Metabolites | CD 13896 | 44.9 nmol/L | Geometric Coefficient of Variation 33.3 |
| Poor Metabolisers: Ref. Treatment | Cmax of BI 409306 and Its Metabolites | BI 409306 | 564 nmol/L | Geometric Coefficient of Variation 50.5 |
| Poor Metabolisers: Ref. Treatment | Cmax of BI 409306 and Its Metabolites | CD 14084 | 470 nmol/L | Geometric Coefficient of Variation 35.8 |
| Poor Metabolisers: Test Treatment | Cmax of BI 409306 and Its Metabolites | BI 409306 | 432 nmol/L | Geometric Coefficient of Variation 35.4 |
| Poor Metabolisers: Test Treatment | Cmax of BI 409306 and Its Metabolites | CD 14084 | 505 nmol/L | Geometric Coefficient of Variation 20.3 |
| Poor Metabolisers: Test Treatment | Cmax of BI 409306 and Its Metabolites | CD 13896 | 42.8 nmol/L | Geometric Coefficient of Variation 16.2 |
Comparison: Analysis for BI 40930690% CI: [80.377, 108.217]
Comparison: Analysis for BI 40930690% CI: [60.482, 97.141]
Comparison: Analysis for CD 1389690% CI: [67.304, 92.052]
Comparison: Analysis for CD 1389690% CI: [81.092, 111.964]
Comparison: Analysis for CD 1408490% CI: [80.731, 93.309]
Comparison: Analysis for CD 1408490% CI: [91.764, 125.812]
Secondary
AUC0-tz of BI 409306 and Its Metabolites
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable plasma concentration (AUC0-tz) of BI 409306 and its metabolites CD 13896 and CD 14084
Time frame: 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Extensive Metabolisers: Ref. Treatment | AUC0-tz of BI 409306 and Its Metabolites | CD 14084 | 2120 nmol*h/L | Geometric Coefficient of Variation 11 |
| Extensive Metabolisers: Ref. Treatment | AUC0-tz of BI 409306 and Its Metabolites | CD 13896 | 388 nmol*h/L | Geometric Coefficient of Variation 26.7 |
| Extensive Metabolisers: Ref. Treatment | AUC0-tz of BI 409306 and Its Metabolites | BI 409306 | 546 nmol*h/L | Geometric Coefficient of Variation 71.6 |
| Extensive Metabolisers: Test Treatment | AUC0-tz of BI 409306 and Its Metabolites | CD 14084 | 2110 nmol*h/L | Geometric Coefficient of Variation 12.6 |
| Extensive Metabolisers: Test Treatment | AUC0-tz of BI 409306 and Its Metabolites | BI 409306 | 620 nmol*h/L | Geometric Coefficient of Variation 68.8 |
| Extensive Metabolisers: Test Treatment | AUC0-tz of BI 409306 and Its Metabolites | CD 13896 | 345 nmol*h/L | Geometric Coefficient of Variation 19.4 |
| Poor Metabolisers: Ref. Treatment | AUC0-tz of BI 409306 and Its Metabolites | BI 409306 | 1560 nmol*h/L | Geometric Coefficient of Variation 45.5 |
| Poor Metabolisers: Ref. Treatment | AUC0-tz of BI 409306 and Its Metabolites | CD 14084 | 1810 nmol*h/L | Geometric Coefficient of Variation 15.7 |
| Poor Metabolisers: Ref. Treatment | AUC0-tz of BI 409306 and Its Metabolites | CD 13896 | 176 nmol*h/L | Geometric Coefficient of Variation 20 |
| Poor Metabolisers: Test Treatment | AUC0-tz of BI 409306 and Its Metabolites | CD 13896 | 163 nmol*h/L | Geometric Coefficient of Variation 14.3 |
| Poor Metabolisers: Test Treatment | AUC0-tz of BI 409306 and Its Metabolites | CD 14084 | 1890 nmol*h/L | Geometric Coefficient of Variation 14.2 |
| Poor Metabolisers: Test Treatment | AUC0-tz of BI 409306 and Its Metabolites | BI 409306 | 1370 nmol*h/L | Geometric Coefficient of Variation 39.4 |
Comparison: Analysis for BI 40930690% CI: [100.505, 128.427]
Comparison: Analysis for BI 40930690% CI: [77.763, 99.37]
Comparison: Analysis for CD 1389690% CI: [84.478, 93.859]
Comparison: Analysis for CD 1389690% CI: [88.278, 96.889]
Comparison: Analysis for CD 1408490% CI: [95.791, 103.583]
Comparison: Analysis for CD 1408490% CI: [98.861, 110.336]
Secondary
t1/2 of BI 409306 and Its Metabolites
Terminal half-life of the analyte in plasma (t1/2) of BI 409306 and its metabolites CD 13896 and CD 14084
Time frame: 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Extensive Metabolisers: Ref. Treatment | t1/2 of BI 409306 and Its Metabolites | BI 409306 | 1.54 Hours | Geometric Coefficient of Variation 16.9 |
| Extensive Metabolisers: Ref. Treatment | t1/2 of BI 409306 and Its Metabolites | CD 14084 | 3.13 Hours | Geometric Coefficient of Variation 22.5 |
| Extensive Metabolisers: Ref. Treatment | t1/2 of BI 409306 and Its Metabolites | CD 13896 | 2.51 Hours | Geometric Coefficient of Variation 21.4 |
| Extensive Metabolisers: Test Treatment | t1/2 of BI 409306 and Its Metabolites | BI 409306 | 1.73 Hours | Geometric Coefficient of Variation 27.3 |
| Extensive Metabolisers: Test Treatment | t1/2 of BI 409306 and Its Metabolites | CD 14084 | 2.62 Hours | Geometric Coefficient of Variation 10.1 |
| Extensive Metabolisers: Test Treatment | t1/2 of BI 409306 and Its Metabolites | CD 13896 | 2.16 Hours | Geometric Coefficient of Variation 21.1 |
| Poor Metabolisers: Ref. Treatment | t1/2 of BI 409306 and Its Metabolites | CD 13896 | 2.26 Hours | Geometric Coefficient of Variation 20.7 |
| Poor Metabolisers: Ref. Treatment | t1/2 of BI 409306 and Its Metabolites | BI 409306 | 2.87 Hours | Geometric Coefficient of Variation 64.1 |
| Poor Metabolisers: Ref. Treatment | t1/2 of BI 409306 and Its Metabolites | CD 14084 | 3.21 Hours | Geometric Coefficient of Variation 39.9 |
| Poor Metabolisers: Test Treatment | t1/2 of BI 409306 and Its Metabolites | BI 409306 | 2.01 Hours | Geometric Coefficient of Variation 25.2 |
| Poor Metabolisers: Test Treatment | t1/2 of BI 409306 and Its Metabolites | CD 14084 | 2.57 Hours | Geometric Coefficient of Variation 19.7 |
| Poor Metabolisers: Test Treatment | t1/2 of BI 409306 and Its Metabolites | CD 13896 | 2.17 Hours | Geometric Coefficient of Variation 16.8 |
Secondary
Tmax of BI 409306 and Its Metabolites
Time from dosing to the maximum concentration of the analyte in plasma (tmax) of BI 409306 and its metabolites CD 13896 and CD 14084
Time frame: 1 hour (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 3h, 4h, 7h, 10h, 12h, 14h, 24h, 48h and 72h (only for test treatment) after drug administration
Population: PKS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Extensive Metabolisers: Ref. Treatment | Tmax of BI 409306 and Its Metabolites | CD 13896 | 1.13 Hours |
| Extensive Metabolisers: Ref. Treatment | Tmax of BI 409306 and Its Metabolites | CD 14084 | 1.75 Hours |
| Extensive Metabolisers: Ref. Treatment | Tmax of BI 409306 and Its Metabolites | BI 409306 | 1.13 Hours |
| Extensive Metabolisers: Test Treatment | Tmax of BI 409306 and Its Metabolites | BI 409306 | 1.75 Hours |
| Extensive Metabolisers: Test Treatment | Tmax of BI 409306 and Its Metabolites | CD 14084 | 2.00 Hours |
| Extensive Metabolisers: Test Treatment | Tmax of BI 409306 and Its Metabolites | CD 13896 | 2.00 Hours |
| Poor Metabolisers: Ref. Treatment | Tmax of BI 409306 and Its Metabolites | CD 14084 | 2.00 Hours |
| Poor Metabolisers: Ref. Treatment | Tmax of BI 409306 and Its Metabolites | CD 13896 | 1.25 Hours |
| Poor Metabolisers: Ref. Treatment | Tmax of BI 409306 and Its Metabolites | BI 409306 | 1.00 Hours |
| Poor Metabolisers: Test Treatment | Tmax of BI 409306 and Its Metabolites | CD 14084 | 2.50 Hours |
| Poor Metabolisers: Test Treatment | Tmax of BI 409306 and Its Metabolites | CD 13896 | 2.00 Hours |
| Poor Metabolisers: Test Treatment | Tmax of BI 409306 and Its Metabolites | BI 409306 | 2.00 Hours |