Renal Insufficiency
Conditions
Brief summary
The primary objective of the current study is to investigate the influence of moderate to severe renal impairment on the pharmacokinetics and safety of a single dose afatinib in comparison to a control group with normal renal function. The assessment of safety and tolerability will be an additional objective of this trial and will be evaluated by descriptive statistics.
Interventions
DRUGAfatinib healthy
DRUGAfatinib severe renally impaired
DRUGAfatinib moderate renally impaired
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
* Despite renal impairment (group 1 and 2) healthy males or females according to the investigators assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests. * Glomerular filtration rate (GFR), estimated according to: \-- MDRD (Modification of Diet in Renal Disease)-formula: * eGFR (estimated Glomerular Filtration Rate) \[ml/min/1.73m²\]= 175 x Serum Creatinine-1.154 x age-0.203 (if male) * eGFR\[ml/min/1.73m²\]= 175 x Serum Creatinine-1.154 x age-0.203 x 0.742 (if female) * 30 to 59 mL/min for moderate renal impairment group 1 * 15 to 29 mL/min for severe renal impairment group 2 * = 90 mL/min for healthy volunteers group 3 * Age =18 and =79 years
Exclusion criteria
* Any finding of the medical examination (including Blood Pressure (BP), Pulse Rate (PR) and Electrocardiogram (ECG)) deviating from normal and of clinical relevance, e.g. repeated measurement of systolic blood pressure \< 90 mmHg (millimeter of mercury) or \> 140 mmHg, diastolic blood pressure \< 50 mmHg or \> 90 mmHg, repeated measurement of pulse rate \< 45 bpm (beats per minute) or \> 90 bpm. * Any evidence of a clinically relevant concomitant disease. * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, dermatological or hormonal disorders. * Relevant gastrointestinal tract surgery (except appendectomy). * Diseases of the central nervous system (such as epilepsy, seizures) or psychiatric disorders or neurological disorders. * History of photosensitivity or recurrent rash. * Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC 0-tz of Afatinib (BIBW 2992) | PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point |
| Cmax of Afatinib (BIBW 2992) | PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration | Maximum measured concentration of the analyte in plasma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC 0-inf of Afatinib (BIBW 2992) | PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity |
Countries
Germany
Participant flow
Recruitment details
30 patients were entered, treated and analyzed.
Pre-assignment details
This was a non-randomised, non-controlled, open-label, single-dose trial with matched group design. Group 1 contained subjects with moderate renal impairment, Group 2 subjects with severe renal impairment, and Group 3 subjects with normal renal function; groups were dosed sequentially.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib in Moderate Renal Impairment Single Dose of 40 mg Afatinib film-coated tablet was orally administered to moderately renally impaired subjects in fasted state with 240 mL of water | 8 |
| Afatinib in Severe Renal Impairment Single Dose of 40 mg Afatinib film-coated tablet was orally administered to severely renally impaired subjects in fasted state with 240 mL of water | 8 |
| Afatinib in Healthy Subjects Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to moderate and severe renal impaired subjects | 14 |
| Total | 30 |
Baseline characteristics
| Characteristic | Afatinib in Moderate Renal Impairment | Afatinib in Severe Renal Impairment | Afatinib in Healthy Subjects | Total |
|---|---|---|---|---|
| Age, Continuous | 68.6 Years STANDARD_DEVIATION 11 | 61.0 Years STANDARD_DEVIATION 11.9 | 62.1 Years STANDARD_DEVIATION 11.4 | 63.6 Years STANDARD_DEVIATION 11.5 |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 7 Participants | 16 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 | 4 / 14 | 2 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 14 | 0 / 8 | 0 / 8 |
Outcome results
Primary
AUC 0-tz of Afatinib (BIBW 2992)
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point
Time frame: PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration
Population: The pharmacokinetic set (PKS): included all patients in the treated set who provided evaluable data for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib in Moderate Renal Impairment | AUC 0-tz of Afatinib (BIBW 2992) | 948 ng*h/mL | Geometric Coefficient of Variation 32.9 |
| Afatinib in Severe Renal Impairment | AUC 0-tz of Afatinib (BIBW 2992) | 952 ng*h/mL | Geometric Coefficient of Variation 31.3 |
| Afatinib in Healthy Subjects Matched to Moderate | AUC 0-tz of Afatinib (BIBW 2992) | 776 ng*h/mL | Geometric Coefficient of Variation 22.9 |
| Afatinib in Healthy Subjects Matched to Severe | AUC 0-tz of Afatinib (BIBW 2992) | 634 ng*h/mL | Geometric Coefficient of Variation 50.8 |
Comparison: The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.90% CI: [95.743, 156.045]ANOVA
Comparison: The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.90% CI: [105.266, 213.671]ANOVA
Primary
Cmax of Afatinib (BIBW 2992)
Maximum measured concentration of the analyte in plasma
Time frame: PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration
Population: The pharmacokinetic set (PKS): included all patients in the treated set who provided evaluable data for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib in Moderate Renal Impairment | Cmax of Afatinib (BIBW 2992) | 28.7 ng/mL | Geometric Coefficient of Variation 44 |
| Afatinib in Severe Renal Impairment | Cmax of Afatinib (BIBW 2992) | 28.2 ng/mL | Geometric Coefficient of Variation 24.5 |
| Afatinib in Healthy Subjects Matched to Moderate | Cmax of Afatinib (BIBW 2992) | 28.3 ng/mL | Geometric Coefficient of Variation 32.2 |
| Afatinib in Healthy Subjects Matched to Severe | Cmax of Afatinib (BIBW 2992) | 23.2 ng/mL | Geometric Coefficient of Variation 42.1 |
Comparison: The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.90% CI: [72.931, 140.309]ANOVA
Comparison: The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.90% CI: [90.79, 163.162]ANOVA
Secondary
AUC 0-inf of Afatinib (BIBW 2992)
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity
Time frame: PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration
Population: The pharmacokinetic set (PKS): included all patients in the treated set who provided evaluable data for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib in Moderate Renal Impairment | AUC 0-inf of Afatinib (BIBW 2992) | 976 ng*h/mL | Geometric Coefficient of Variation 32.5 |
| Afatinib in Severe Renal Impairment | AUC 0-inf of Afatinib (BIBW 2992) | 980 ng*h/mL | Geometric Coefficient of Variation 31.9 |
| Afatinib in Healthy Subjects Matched to Moderate | AUC 0-inf of Afatinib (BIBW 2992) | 797 ng*h/mL | Geometric Coefficient of Variation 22.7 |
| Afatinib in Healthy Subjects Matched to Severe | AUC 0-inf of Afatinib (BIBW 2992) | 653 ng*h/mL | Geometric Coefficient of Variation 49.8 |
Comparison: The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.90% CI: [96.141, 155.928]ANOVA
Comparison: The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.90% CI: [105.626, 213.25]ANOVA