Healthy, Liver Diseases
Conditions
Brief summary
Up to 38 subjects entered with the aim of entering 8 subjects with mild liver impairment (at highest dose of afatinib), 8 subjects with moderate liver impairment (at either highest dose or two lower doses) and 8 healthy matched controls to each of this two groups.
Interventions
DRUGAfatinib
1 tablet, once qd in the morning
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy subjects: 1. Healthy males and females according to a complete medical history, including a physical examination, vital signs (Blood Pressure, Pulse Rate), 12-lead Electrocardiogram, and clinical laboratory tests. The healthy subjects must meet the matching criteria based on the matching approach (cf. Section 3.3). 2. Age =18 and =75 years 3. Body Mass Index =18.5 and =34 kg/m2 4. Creatinine clearance \>70 mL/min according to Cockroft & Gault (for healthy volunteers, cf. Section 10.2) 5. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation. Hepatically impaired subjects as determined by a hepatologist/ gastroenterologist: 6. Male and female liver impaired subjects determined by results of screening classified as Child-Pugh A; Child-Pugh score of 5-6 points or as Child-Pugh B; Child-Pugh score of 7-9 points, cf. Section 10.2. Child-Pugh criteria must be stable for at least 3 months prior to screening and during the trial. 7. Age =18 and =75 years 8. Body Mass Index =18.5 and =34 kg/m2 9. Creatinine clearance \>40 mL/min according to Cockroft & Gault (for liver impaired subjects, cf. Section 10.2) 10. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation. For all females: 11. Postmenopausal female subjects (postmenopausal defined as at least 1 year of spontaneous amenorrhea \[in questionable cases or spontaneous amenorrhea below 1 year a blood sample with simultaneous follicle stimulating hormone (FSH) above 40 IU/l and estradiol below 30 ng/l is confirmatory\]) or adequate contraception\* for female subjects of childbearing potential during the study and until 2 months after study completion, e.g. any of the following: implants, injectables, combined oral contraceptives, IUD (intrauterine device), sexual abstinence for at least 1 month prior to first study drug administration, vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (including hysterectomy). Females, who do not have a vasectomised partner, are not sexually abstinent or surgically sterile have to use an additional barrier method (e.g. condom).
Exclusion criteria
Any relevant deviation from healthy conditions (excluded conditions caused by liver impairment)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Curve From 0 to Infinity (AUC0-infinity) | 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing | AUC0-infinity represents the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity |
| Maximum Concentration (Cmax) | 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing | Cmax represents the maximum measured concentration of the analyte in plasma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Curve From 0 to tz (AUC0-tz) | 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing | AUC0-tz represents the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point |
| Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | First administration of trial medication until 28 days after last administration of trial medication | Clinical relevant abnormalitites for physical examination, vital signs, 12-lead electrocardiogramm (ECG), clinical laboratory test (including hematology, clinical chemistry, coagulation, urinalysis), adverse event, investigator's global tolerability. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 50 mg Afatinib Group A Group A: Mild hepatic impaired subjects with Child Pugh A were treated with 50 mg Afatinib (One tablet qd in the morning). | 8 |
| 30 mg Afatinib Group B1 Group B1: Moderate hepatic impaired subjects with Child Pugh B were treated with 30 mg Afatinib (One tablet qd in the morning). | 3 |
| 50 mg Afatinib Group B2 Group B2: Moderate hepatic impaired subjects with Child Pugh B were treated with 50 mg Afatinib (One tablet qd in the morning). | 8 |
| 50 mg Afatinib Group C Group C: Subjects with normal hepatic function matching to subjects in group A were treated with 50 mg Afatinib (One tablet qd in the morning). | 8 |
| 50 mg Afatinib Group D Group D: Subjects with normal hepatic function matching to subjects in group B2 were treated with 50 mg Afatinib (One tablet qd in the morning). | 8 |
| Total | 35 |
Baseline characteristics
| Characteristic | 50 mg Afatinib Group A | 30 mg Afatinib Group B1 | 50 mg Afatinib Group B2 | 50 mg Afatinib Group C | 50 mg Afatinib Group D | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 53.9 years STANDARD_DEVIATION 9 | 64.3 years STANDARD_DEVIATION 6.1 | 54.8 years STANDARD_DEVIATION 9 | 55.9 years STANDARD_DEVIATION 12.6 | 53.1 years STANDARD_DEVIATION 7.9 | 55.3 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 3 Participants | 2 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 6 Participants | 3 Participants | 5 Participants | 6 Participants | 5 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 8 | 1 / 3 | 1 / 8 | 1 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 3 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under Curve From 0 to Infinity (AUC0-infinity)
AUC0-infinity represents the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity
Time frame: 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing
Population: Pharmacokinetic (PK) analysis set includes all evaluable matched subjects in the treated set providing at least 1 observation for at least 1 PK endpoint without important protocol violations. Group B1 was not included in the primary analysis set for comparison.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 50 mg Afatinib Group A | Area Under Curve From 0 to Infinity (AUC0-infinity) | 886 ng*h/mL | Geometric Coefficient of Variation 53.7 |
| 30 mg Afatinib Group B1 | Area Under Curve From 0 to Infinity (AUC0-infinity) | 552 ng*h/mL | Geometric Coefficient of Variation 42.1 |
| 50 mg Afatinib Group B2 | Area Under Curve From 0 to Infinity (AUC0-infinity) | 934 ng*h/mL | Geometric Coefficient of Variation 31 |
| 50 mg Afatinib Group C | Area Under Curve From 0 to Infinity (AUC0-infinity) | 956 ng*h/mL | Geometric Coefficient of Variation 22.7 |
| 50 mg Afatinib Group D | Area Under Curve From 0 to Infinity (AUC0-infinity) | 985 ng*h/mL | Geometric Coefficient of Variation 32.3 |
p-value: 0.199890% CI: [67.96, 126.27]ANOVA
p-value: 0.14490% CI: [72.278, 124.549]ANOVA
Primary
Maximum Concentration (Cmax)
Cmax represents the maximum measured concentration of the analyte in plasma
Time frame: 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing
Population: PK analysis set. Group B1 was not included in the primary analysis set for comparison.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 50 mg Afatinib Group A | Maximum Concentration (Cmax) | 33.7 ng/mL | Geometric Coefficient of Variation 51.7 |
| 30 mg Afatinib Group B1 | Maximum Concentration (Cmax) | 17.5 ng/mL | Geometric Coefficient of Variation 44.1 |
| 50 mg Afatinib Group B2 | Maximum Concentration (Cmax) | 39.5 ng/mL | Geometric Coefficient of Variation 40.1 |
| 50 mg Afatinib Group C | Maximum Concentration (Cmax) | 30.7 ng/mL | Geometric Coefficient of Variation 33.7 |
| 50 mg Afatinib Group D | Maximum Concentration (Cmax) | 31.1 ng/mL | Geometric Coefficient of Variation 46 |
p-value: 0.200290% CI: [82.683, 144.947]ANOVA
p-value: 0.528190% CI: [86.028, 187.159]ANOVA
Secondary
Area Under Curve From 0 to tz (AUC0-tz)
AUC0-tz represents the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point
Time frame: 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing
Population: PK analysis set. Group B1 was not included in the primary analysis set for comparison.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 50 mg Afatinib Group A | Area Under Curve From 0 to tz (AUC0-tz) | 842 ng*h/mL | Geometric Coefficient of Variation 50.8 |
| 30 mg Afatinib Group B1 | Area Under Curve From 0 to tz (AUC0-tz) | 519 ng*h/mL | Geometric Coefficient of Variation 39.1 |
| 50 mg Afatinib Group B2 | Area Under Curve From 0 to tz (AUC0-tz) | 904 ng*h/mL | Geometric Coefficient of Variation 31.4 |
| 50 mg Afatinib Group C | Area Under Curve From 0 to tz (AUC0-tz) | 930 ng*h/mL | Geometric Coefficient of Variation 22.5 |
| 50 mg Afatinib Group D | Area Under Curve From 0 to tz (AUC0-tz) | 956 ng*h/mL | Geometric Coefficient of Variation 33.3 |
p-value: 0.230990% CI: [66.915, 122.705]ANOVA
p-value: 0.154690% CI: [71.563, 124.764]ANOVA
Secondary
Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability
Clinical relevant abnormalitites for physical examination, vital signs, 12-lead electrocardiogramm (ECG), clinical laboratory test (including hematology, clinical chemistry, coagulation, urinalysis), adverse event, investigator's global tolerability. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.
Time frame: First administration of trial medication until 28 days after last administration of trial medication
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50 mg Afatinib Group A | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Hyperlipasaemia | 0 participants |
| 50 mg Afatinib Group A | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Lipase increased | 1 participants |
| 30 mg Afatinib Group B1 | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Lipase increased | 0 participants |
| 30 mg Afatinib Group B1 | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Hyperlipasaemia | 1 participants |
| 50 mg Afatinib Group B2 | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Lipase increased | 0 participants |
| 50 mg Afatinib Group B2 | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Hyperlipasaemia | 0 participants |
| 50 mg Afatinib Group C | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Lipase increased | 0 participants |
| 50 mg Afatinib Group C | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Hyperlipasaemia | 0 participants |
| 50 mg Afatinib Group D | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Hyperlipasaemia | 0 participants |
| 50 mg Afatinib Group D | Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability | Lipase increased | 0 participants |