Hepatic Insufficiency
Conditions
Brief summary
The primary objective of this study is to investigate the effect of mild (Child-Pugh A, score 5-6) and moderate (Child-Pugh B, score 7-9) hepatic impairment on the pharmacokinetics, safety and tolerability of nintedanib, in comparison with a control group with normal hepatic function following oral administration of nintedanib as single dose.
Interventions
DRUGNintedanib
Soft gelatine capsule
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy subjects: * Male or female subject, healthy according to the investigator's judgement based on a complete medical history, including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory * Age of 18 to 79 years at screening visit Hepatically impaired patients as determined by a hepatologist/ gastroenterologist: * A documented diagnosis of the impaired hepatic function, determined by hepatologist/gastroenterologist/specialist for internal medicine, must be available in the patient´s source data. * Male or female chronic hepatically impaired patient as determined by screening results and classified as Child-Pugh A (Child-Pugh score of 5-6 points) or as Child-Pugh B (Child-Pugh score of 7-9 points). Hepatic insufficiency must be diagnosed at least 3 months before screening. * Age of 18 to 79 years at screening visit
Exclusion criteria
Healthy subjects: * Any finding in the medical examination (including BP, PR or ECG) deviating from normal and judged as clinically relevant by the investigator * Any laboratory value outside the reference range at screening visit that the investigator considers to be of clinical relevance * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders judged as clinically relevant by the investigator * Surgery of the gastrointestinal tract that could interfere with kinetics of the trial medication based on the investigator´s judgment * Women who are breast feeding or of child-bearing potential not using a highly effective method of birth control for at least one month prior to inclusion and at least 3 month after administration of trial medication. Hepatically impaired patients as determined by a hepatologist/gastroenterologist: * Medical disorder, condition or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator or the sponsor * Patients with significant diseases other than underlying diagnose of hepatic impairment and concomitant diseases related to it. A significant disease is defined as a disease which in the opinion of the investigator: * put the patient at risk because of participation in the study * may influence the results of the study * is not in a stable condition * Surgery of the gastrointestinal tract that could interfere with the kinetics of the trial medication based on the investigator´s judgment * Women who are breast feeding or of child-bearing potential not using a highly effective method of birth control for at least one month prior to inclusion and at least 3 month after administration of trial medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-inf) of Nintedanib | Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration | AUC (0-inf) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 extrapolated to infinity) |
| Cmax of Nintedanib | Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration | Cmax (Maximum measured concentration of the Nintedanib in plasma) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-tz) of Nintedanib | Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration | AUC (0-tz) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 to the last quantifiable drug plasma concentration) |
| Number (%) of Subjects With Drug-related Adverse Events (AEs) | (AEs) during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); Up to 29 days | Number (%) of subjects with drug-related Adverse events (AEs) |
Countries
Germany
Participant flow
Recruitment details
Healthy subjects were to be matched to subjects with hepatic impairment ((Child-Pugh A, score 5 or 6),(Child-Pugh B, score 7 to 9)) by age (±10 years), body weight (±10%), sex, race, and smoking habits (current vs. ex- and never smokers).
Participants by arm
| Arm | Count |
|---|---|
| Child Pugh A Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).
Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group. | 8 |
| Child Pugh B Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).
Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group. | 8 |
| Healthy Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function. | 17 |
| Total | 33 |
Baseline characteristics
| Characteristic | Child Pugh A | Child Pugh B | Healthy | Total |
|---|---|---|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 8.1 | 56.6 years STANDARD_DEVIATION 6.5 | 57.6 years STANDARD_DEVIATION 8.4 | 58.1 years STANDARD_DEVIATION 7.8 |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 3 / 8 | 3 / 17 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 17 |
Outcome results
Primary
AUC (0-inf) of Nintedanib
AUC (0-inf) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 extrapolated to infinity)
Time frame: Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration
Population: Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child-Pugh A | AUC (0-inf) of Nintedanib | 200 ng*h/mL | Geometric Coefficient of Variation 87.7 |
| Child-Pugh B | AUC (0-inf) of Nintedanib | 674 ng*h/mL | Geometric Coefficient of Variation 66.3 |
| Healthy Matched Child-Pugh A | AUC (0-inf) of Nintedanib | 92.7 ng*h/mL | Geometric Coefficient of Variation 58.5 |
| Healthy Matched Child-Pugh B | AUC (0-inf) of Nintedanib | 77.8 ng*h/mL | Geometric Coefficient of Variation 38.2 |
Comparison: The statistical model used for the analysis of AUC (0-inf) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.90% CI: [120.71, 384.32]ANOVA
Comparison: The statistical model used for the analysis of AUC (0-inf) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.90% CI: [572.93, 1312.41]ANOVA
Primary
Cmax of Nintedanib
Cmax (Maximum measured concentration of the Nintedanib in plasma)
Time frame: Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration
Population: Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child-Pugh A | Cmax of Nintedanib | 20.5 ng/mL | Geometric Coefficient of Variation 68.4 |
| Child-Pugh B | Cmax of Nintedanib | 59.4 ng/mL | Geometric Coefficient of Variation 87 |
| Healthy Matched Child-Pugh A | Cmax of Nintedanib | 9.25 ng/mL | Geometric Coefficient of Variation 54.1 |
| Healthy Matched Child-Pugh B | Cmax of Nintedanib | 7.81 ng/mL | Geometric Coefficient of Variation 49.3 |
Comparison: The statistical model used for the analysis of Cmax was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.90% CI: [134.73, 365.01]ANOVA
Comparison: The statistical model used for the analysis of Cmax was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.90% CI: [439.01, 1319.18]ANOVA
Secondary
AUC (0-tz) of Nintedanib
AUC (0-tz) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 to the last quantifiable drug plasma concentration)
Time frame: Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration
Population: Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Child-Pugh A | AUC (0-tz) of Nintedanib | 193 ng*h/mL | Geometric Coefficient of Variation 89.5 |
| Child-Pugh B | AUC (0-tz) of Nintedanib | 652 ng*h/mL | Geometric Coefficient of Variation 66.2 |
| Healthy Matched Child-Pugh A | AUC (0-tz) of Nintedanib | 89.2 ng*h/mL | Geometric Coefficient of Variation 59.6 |
| Healthy Matched Child-Pugh B | AUC (0-tz) of Nintedanib | 74.8 ng*h/mL | Geometric Coefficient of Variation 38.9 |
Comparison: The statistical model used for the analysis of AUC (0-tz) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.90% CI: [120.37, 390.45]ANOVA
Comparison: The statistical model used for the analysis of AUC (0-tz) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.90% CI: [576.36, 1315.49]ANOVA
Secondary
Number (%) of Subjects With Drug-related Adverse Events (AEs)
Number (%) of subjects with drug-related Adverse events (AEs)
Time frame: (AEs) during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); Up to 29 days
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Child-Pugh A | Number (%) of Subjects With Drug-related Adverse Events (AEs) | 0.0 percentage of participants |
| Child-Pugh B | Number (%) of Subjects With Drug-related Adverse Events (AEs) | 37.5 percentage of participants |
| Healthy Matched Child-Pugh A | Number (%) of Subjects With Drug-related Adverse Events (AEs) | 17.6 percentage of participants |