Healthy
Conditions
Brief summary
The main objectives of this trial are: * To evaluate the effect of BI 474121 on cyclic guanosine monophosphate (cGMP) levels in cerebrospinal fluid (CSF) * To assess the exposure of BI 474121 in CSF relative to plasma * To determine the exposure effect relationship in CSF with different oral doses of BI 474121
Interventions
DRUGPlacebo
Placebo matching to 10 mg BI 474121 administered as uncoated tablets with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 1: randomised, placebo-controlled, single-blind.
DRUG2.5 milligram (mg) BI 474121
2.5 mg BI 474121 administered as uncoated tablets (1 x 2.5 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 3 of the study: randomised, open-label.
DRUG10 milligram (mg) BI 474121
10 mg BI 474121 administered as uncoated tablets (1 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 3 of the study: randomised, open-label.
DRUG20 milligram (mg) BI 474121
20 mg BI 474121 administered as uncoated tablets (2 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 1 of the study: randomised, placebo-controlled, single-blind.
DRUG40 milligram (mg) BI 474121
40 mg BI 474121 administered as uncoated tablets (4 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 2 of the study: non-randomised, open-label.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention model description
This trial is designed to have three parts. Part 1: single-blind, randomized, placebo-controlled. Part 2: open-label, non-randomized. Part 3: open-label, randomized.
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 65 years (inclusive) * BMI of 18.5 to 29.9 kg/m2 (inclusive) * Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 150 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease assessed as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders assessed as clinically relevant by the investigator * Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * History of relevant orthostatic hypotension, fainting spells, or blackouts * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Exposure-related Change From Baseline (Calculated as Ratio) of Cyclic Guanosine Monophosphate (cGMP) in Cerebrospinal Fluid (CSF) | Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration. | Maximum exposure-related change from baseline (calculated as ratio) of cyclic guanosine monophosphate (cGMP) in Cerebrospinal fluid (CSF). In subjects treated with BI 474121 this is the maximum cGMP value measured within 1 hour (h) prior and 4 h post BI 474121 Maximum measured concentration (Cmax) in CSF. For subjects treated with placebo, this is the maximum cGMP value measured within 1 h prior to and 4 h after the median BI 474121 tmax (time from (last) dosing to the maximum measured concentration of the analyte) in CSF of the BI 474121 treated subjects. Baseline cGMP concentration was calculated as the arithmetic mean of all pre-dose measurements above Lower limit of quantification (LLOQ) obtained in that subject. The maximum exposure-related change from baseline in cGMP in CSF was explored using an analysis of covariance (ANCOVA) model on the logarithmic scale. Maximum exposure related cGMP: Ratio \[maximum cGMP / baseline cGMP\]. |
| Maximum Measured Concentration (Cmax) Ratio of BI 474121 in Cerebrospinal Fluid (CSF) Compared to Plasma | Up to 72 hours, see endpoint description for detailed sampling scheme. | Maximum measured concentration (Cmax) ratio of BI 474121 in CSF compared to plasma. Mixed effects model: random effect 'subject nested within treatment', fixed effect, treatment, substance and their interaction' (for estimation of overall group effect the model was run without interaction term). Cmax was log transformed (natural logarithm) prior to fitting the model. Difference between expected means for log(CSF)- log(plasma) was estimated by difference in the corresponding least square means (point estimate) and two-sided 90% CI based on the t-distribution were computed. Quantities were back-transformed to the original scale to give an point estimator and interval estimate. Ratio = CSF (T) / plasma (R). Plasma: Within 3 hours (h) before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 h following drug administration. CSF: Within approximately 2, 1, and 0.17 h before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 h following drug administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Dosing to Maximum Measured BI 474121 Concentrations in Plasma (Tmax) | Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 hours following drug administration. | Time from dosing to maximum measured BI 474121 concentrations in plasma (tmax). |
| Maximum Measured Concentration (Cmax) of BI 474121 in Plasma | Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 hours following drug administration. | Maximum measured concentration (Cmax) of BI 474121 in plasma. |
| Maximum Measured Exposure-related cGMP Concentration in Cerebrospinal Fluid (CSF) | Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration. | Maximum measured exposure-related cGMP concentration in CSF. In subjects treated with BI 474121 this is the maximum cGMP value measured within 1 hour (h) prior and 4 h post BI 474121 Maximum measured concentration (Cmax) in CSF. For subjects treated with placebo, this is the maximum cGMP value measured within 1 h prior to and 4 h after the median BI 474121 tmax (time from (last) dosing to the maximum measured concentration of the analyte) in CSF of the BI 474121 treated subjects. |
| Time From Dosing to Maximum Measured BI 474121 Concentrations in CSF (Tmax) | Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration. | Time from dosing to maximum measured BI 474121 concentrations in CSF (tmax). |
| Maximum Measured Concentration (Cmax) of BI 474121 in Cerebrospinal Fluid (CSF) | Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration. | Maximum measured concentration (Cmax) of BI 474121 in Cerebrospinal fluid (CSF). |
Countries
Netherlands
Participant flow
Recruitment details
This study consisted of three parts, part 1: randomised, placebo-controlled, single-blind, part 2:non-randomised, open-label and part 3: randomised, open-label, with the aim of exploring the pharmacokinetics and pharmacodynamic effects of different single oral doses of BI 474121 in healthy male subjects
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matching to 10 mg BI 474121 administered as uncoated tablets with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 1: randomised, placebo-controlled, single-blind. | 4 |
| 2.5 Milligram (mg) BI 474121 2.5 mg BI 474121 administered as uncoated tablets (1 x 2.5 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 3 of the study: randomised, open-label. | 4 |
| 10 Milligram (mg) BI 474121 10 mg BI 474121 administered as uncoated tablets (1 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 3 of the study: randomised, open-label. | 4 |
| 20 Milligram (mg) BI 474121 20 mg BI 474121 administered as uncoated tablets (2 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 1 of the study: randomised, placebo-controlled, single-blind. | 6 |
| 40 Milligram (mg) BI 474121 40 mg BI 474121 administered as uncoated tablets (4 x 10 mg) with 240 milliliter of water after subjects fasted overnight for at least 10 hours. This arm was part of Part 2 of the study: non-randomised, open-label. | 6 |
| Total | 24 |
Baseline characteristics
| Characteristic | Placebo | 2.5 Milligram (mg) BI 474121 | 10 Milligram (mg) BI 474121 | 20 Milligram (mg) BI 474121 | 40 Milligram (mg) BI 474121 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 24.3 | 27.5 years STANDARD_DEVIATION 9.3 | 22.0 years STANDARD_DEVIATION 3.2 | 38.3 years STANDARD_DEVIATION 17.4 | 23.2 years STANDARD_DEVIATION 2.9 | 30.5 years STANDARD_DEVIATION 14.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 4 Participants | 6 Participants | 6 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 4 Participants | 5 Participants | 5 Participants | 21 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 6 Participants | 6 Participants | 24 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 4 / 4 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Maximum Exposure-related Change From Baseline (Calculated as Ratio) of Cyclic Guanosine Monophosphate (cGMP) in Cerebrospinal Fluid (CSF)
Maximum exposure-related change from baseline (calculated as ratio) of cyclic guanosine monophosphate (cGMP) in Cerebrospinal fluid (CSF). In subjects treated with BI 474121 this is the maximum cGMP value measured within 1 hour (h) prior and 4 h post BI 474121 Maximum measured concentration (Cmax) in CSF. For subjects treated with placebo, this is the maximum cGMP value measured within 1 h prior to and 4 h after the median BI 474121 tmax (time from (last) dosing to the maximum measured concentration of the analyte) in CSF of the BI 474121 treated subjects. Baseline cGMP concentration was calculated as the arithmetic mean of all pre-dose measurements above Lower limit of quantification (LLOQ) obtained in that subject. The maximum exposure-related change from baseline in cGMP in CSF was explored using an analysis of covariance (ANCOVA) model on the logarithmic scale. Maximum exposure related cGMP: Ratio \[maximum cGMP / baseline cGMP\].
Time frame: Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration.
Population: Pharmacodynamic parameter analysis set (PDS): all evaluable subjects who were entered and treated with one dose of study drug and who provided at least one evaluable pre- and post-dose measure for a pharmacodynamic endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Maximum Exposure-related Change From Baseline (Calculated as Ratio) of Cyclic Guanosine Monophosphate (cGMP) in Cerebrospinal Fluid (CSF) | NA maximum change from baseline cGMP ratio |
| 2.5 Milligram (mg) BI 474121 | Maximum Exposure-related Change From Baseline (Calculated as Ratio) of Cyclic Guanosine Monophosphate (cGMP) in Cerebrospinal Fluid (CSF) | NA maximum change from baseline cGMP ratio |
| 10 Milligram (mg) BI 474121 | Maximum Exposure-related Change From Baseline (Calculated as Ratio) of Cyclic Guanosine Monophosphate (cGMP) in Cerebrospinal Fluid (CSF) | NA maximum change from baseline cGMP ratio |
| 20 Milligram (mg) BI 474121 | Maximum Exposure-related Change From Baseline (Calculated as Ratio) of Cyclic Guanosine Monophosphate (cGMP) in Cerebrospinal Fluid (CSF) | NA maximum change from baseline cGMP ratio |
| 40 Milligram (mg) BI 474121 | Maximum Exposure-related Change From Baseline (Calculated as Ratio) of Cyclic Guanosine Monophosphate (cGMP) in Cerebrospinal Fluid (CSF) | NA maximum change from baseline cGMP ratio |
Comparison: The difference between the expected means for ln(T) - ln(R) was estimated by the difference in the corresponding least square means (point estimate) and two-sided 90% confidence intervals based on the t-distribution were computed. These quantities were back-transformed to the original scale to give the point estimator and interval estimates.p-value: 0.394190% CI: [0.78, 2.13]ANCOVA
Comparison: The difference between the expected means for ln(T) - ln(R) was estimated by the difference in the corresponding least square means (point estimate) and two-sided 90% confidence intervals based on the t-distribution were computed. These quantities were back-transformed to the original scale to give the point estimator and interval estimates.p-value: 0.108990% CI: [0.99, 2.79]ANCOVA
Comparison: The difference between the expected means for ln(T) - ln(R) was estimated by the difference in the corresponding least square means (point estimate) and two-sided 90% confidence intervals based on the t-distribution were computed. These quantities were back-transformed to the original scale to give the point estimator and interval estimates.p-value: 0.630890% CI: [0.71, 1.85]ANCOVA
Comparison: The difference between the expected means for ln(T) - ln(R) was estimated by the difference in the corresponding least square means (point estimate) and two-sided 90% confidence intervals based on the t-distribution were computed. These quantities were back-transformed to the original scale to give the point estimator and interval estimates.p-value: 0.06990% CI: [1.06, 2.89]ANCOVA
Primary
Maximum Measured Concentration (Cmax) Ratio of BI 474121 in Cerebrospinal Fluid (CSF) Compared to Plasma
Maximum measured concentration (Cmax) ratio of BI 474121 in CSF compared to plasma. Mixed effects model: random effect 'subject nested within treatment', fixed effect, treatment, substance and their interaction' (for estimation of overall group effect the model was run without interaction term). Cmax was log transformed (natural logarithm) prior to fitting the model. Difference between expected means for log(CSF)- log(plasma) was estimated by difference in the corresponding least square means (point estimate) and two-sided 90% CI based on the t-distribution were computed. Quantities were back-transformed to the original scale to give an point estimator and interval estimate. Ratio = CSF (T) / plasma (R). Plasma: Within 3 hours (h) before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 h following drug administration. CSF: Within approximately 2, 1, and 0.17 h before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 h following drug administration.
Time frame: Up to 72 hours, see endpoint description for detailed sampling scheme.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects who were entered and treated with one dose of study drug and who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Maximum Measured Concentration (Cmax) Ratio of BI 474121 in Cerebrospinal Fluid (CSF) Compared to Plasma | 9.49 Ratio [%] Cmax CSF (T) / Cmax Plasma (R) |
| 2.5 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) Ratio of BI 474121 in Cerebrospinal Fluid (CSF) Compared to Plasma | 7.88 Ratio [%] Cmax CSF (T) / Cmax Plasma (R) |
| 10 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) Ratio of BI 474121 in Cerebrospinal Fluid (CSF) Compared to Plasma | 9.89 Ratio [%] Cmax CSF (T) / Cmax Plasma (R) |
| 20 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) Ratio of BI 474121 in Cerebrospinal Fluid (CSF) Compared to Plasma | 8.42 Ratio [%] Cmax CSF (T) / Cmax Plasma (R) |
| 40 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) Ratio of BI 474121 in Cerebrospinal Fluid (CSF) Compared to Plasma | 8.96 Ratio [%] Cmax CSF (T) / Cmax Plasma (R) |
Secondary
Maximum Measured Concentration (Cmax) of BI 474121 in Cerebrospinal Fluid (CSF)
Maximum measured concentration (Cmax) of BI 474121 in Cerebrospinal fluid (CSF).
Time frame: Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects who were entered and treated with one dose of study drug and who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject will be included in the PKS, even if he/she contributes only one PK parameter value to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Measured Concentration (Cmax) of BI 474121 in Cerebrospinal Fluid (CSF) | 2.09 Nanomol/Liter | Geometric Coefficient of Variation 27.9 |
| 2.5 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) of BI 474121 in Cerebrospinal Fluid (CSF) | 6.87 Nanomol/Liter | Geometric Coefficient of Variation 25.9 |
| 10 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) of BI 474121 in Cerebrospinal Fluid (CSF) | 13.6 Nanomol/Liter | Geometric Coefficient of Variation 9.17 |
| 20 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) of BI 474121 in Cerebrospinal Fluid (CSF) | 23.5 Nanomol/Liter | Geometric Coefficient of Variation 25 |
Secondary
Maximum Measured Concentration (Cmax) of BI 474121 in Plasma
Maximum measured concentration (Cmax) of BI 474121 in plasma.
Time frame: Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 hours following drug administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects who were entered and treated with one dose of study drug and who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject will be included in the PKS, even if he/she contributes only one PK parameter value to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Measured Concentration (Cmax) of BI 474121 in Plasma | 22.0 Nanomol/Liter | Geometric Coefficient of Variation 30 |
| 2.5 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) of BI 474121 in Plasma | 87.2 Nanomol/Liter | Geometric Coefficient of Variation 30.3 |
| 10 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) of BI 474121 in Plasma | 137 Nanomol/Liter | Geometric Coefficient of Variation 21.7 |
| 20 Milligram (mg) BI 474121 | Maximum Measured Concentration (Cmax) of BI 474121 in Plasma | 278 Nanomol/Liter | Geometric Coefficient of Variation 13.4 |
Secondary
Maximum Measured Exposure-related cGMP Concentration in Cerebrospinal Fluid (CSF)
Maximum measured exposure-related cGMP concentration in CSF. In subjects treated with BI 474121 this is the maximum cGMP value measured within 1 hour (h) prior and 4 h post BI 474121 Maximum measured concentration (Cmax) in CSF. For subjects treated with placebo, this is the maximum cGMP value measured within 1 h prior to and 4 h after the median BI 474121 tmax (time from (last) dosing to the maximum measured concentration of the analyte) in CSF of the BI 474121 treated subjects.
Time frame: Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration.
Population: Pharmacodynamic parameter analysis set (PDS): This set includes all evaluable subjects who provide at least one evaluable pre- and post-dose measure for a PD endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Measured Exposure-related cGMP Concentration in Cerebrospinal Fluid (CSF) | 7.51 Nanomol/Liter | Geometric Coefficient of Variation 40 |
| 2.5 Milligram (mg) BI 474121 | Maximum Measured Exposure-related cGMP Concentration in Cerebrospinal Fluid (CSF) | 9.54 Nanomol/Liter | Geometric Coefficient of Variation 32.5 |
| 10 Milligram (mg) BI 474121 | Maximum Measured Exposure-related cGMP Concentration in Cerebrospinal Fluid (CSF) | 10.7 Nanomol/Liter | Geometric Coefficient of Variation 79.2 |
| 20 Milligram (mg) BI 474121 | Maximum Measured Exposure-related cGMP Concentration in Cerebrospinal Fluid (CSF) | 7.36 Nanomol/Liter | Geometric Coefficient of Variation 40.4 |
| 40 Milligram (mg) BI 474121 | Maximum Measured Exposure-related cGMP Concentration in Cerebrospinal Fluid (CSF) | 11.1 Nanomol/Liter | Geometric Coefficient of Variation 37.8 |
Secondary
Time From Dosing to Maximum Measured BI 474121 Concentrations in CSF (Tmax)
Time from dosing to maximum measured BI 474121 concentrations in CSF (tmax).
Time frame: Within approximately 2, 1, and 0.17 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours following drug administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects who were entered and treated with one dose of study drug and who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject will be included in the PKS, even if he/she contributes only one PK parameter value to the statistical assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Dosing to Maximum Measured BI 474121 Concentrations in CSF (Tmax) | 2.03 hours |
| 2.5 Milligram (mg) BI 474121 | Time From Dosing to Maximum Measured BI 474121 Concentrations in CSF (Tmax) | 2.03 hours |
| 10 Milligram (mg) BI 474121 | Time From Dosing to Maximum Measured BI 474121 Concentrations in CSF (Tmax) | 3.02 hours |
| 20 Milligram (mg) BI 474121 | Time From Dosing to Maximum Measured BI 474121 Concentrations in CSF (Tmax) | 4.03 hours |
Secondary
Time From Dosing to Maximum Measured BI 474121 Concentrations in Plasma (Tmax)
Time from dosing to maximum measured BI 474121 concentrations in plasma (tmax).
Time frame: Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 34, 48 and 72 hours following drug administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects who were entered and treated with one dose of study drug and who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject will be included in the PKS, even if he/she contributes only one PK parameter value to the statistical assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Dosing to Maximum Measured BI 474121 Concentrations in Plasma (Tmax) | 4.00 hours |
| 2.5 Milligram (mg) BI 474121 | Time From Dosing to Maximum Measured BI 474121 Concentrations in Plasma (Tmax) | 1.50 hours |
| 10 Milligram (mg) BI 474121 | Time From Dosing to Maximum Measured BI 474121 Concentrations in Plasma (Tmax) | 2.01 hours |
| 20 Milligram (mg) BI 474121 | Time From Dosing to Maximum Measured BI 474121 Concentrations in Plasma (Tmax) | 4.00 hours |