Rheumatoid Arthritis
Conditions
Brief summary
The primary objective of this study is to evaluate the pharmacokinetics (PK) of filgotinib and its metabolite, GS-829845, in participants with varying degrees of impaired hepatic function relative to matched, healthy controls.
Interventions
DRUGFilgotinib
100 mg tablet administered orally
Sponsors
Galapagos NV
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Eligible individuals will be male and nonpregnant, nonlactating females, aged 18 to 70 years (inclusive), body mass index (BMI) between 18 and 36 kg/m\^2 (inclusive), with either impaired hepatic function or normal hepatic function. * Individuals will be current nonsmokers (no use of tobacco, nicotine-containing, or tetrahydrocannabinol \[THC\]-containing products within the last 14 days). * Individuals with hepatic impairment will be categorized by the Child-Pugh-Turcotte (CPT) classification system indicating hepatic impairment as follows: * Class A (mild): CPT score 5-6 * Class B (moderate): CPT score 7-9 * Class C (severe): CPT score 10-15 * Hepatic impairment must have been stable during the 3 months (90 days) prior to study drug. Each individual in the control group will be matched to a individual with impaired hepatic function by age (± 10 years), gender, and body mass index (± 15%). Note: Other protocol defined Inclusion/
Exclusion criteria
may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter: Cmax of GS-829845 | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1 | Cmax is defined as the maximum observed concentration of drug. GS-829845 is the primary metabolite of filgotinib. |
| PK Parameter: AUCinf of GS-829845 | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1 | AUCinf is defined as the concentration of drug extrapolated to infinite time. GS-829845 is the primary metabolite of filgotinib. |
| PK Parameter: Cmax of Filgotinib | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1 | Cmax is defined as the maximum observed concentration of drug. |
| Pharmacokinetic (PK) Parameter: AUClast of Filgotinib | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1 | AUClast is defined as the concentration of drug from time zero to the last observable concentration. |
| PK Parameter: AUClast of GS-829845 | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1 | AUClast is defined as the concentration of drug from time zero to the last observable concentration. GS-829845 is the primary metabolite of filgotinib. |
| PK Parameter: AUCinf of Filgotinib | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1 | AUCinf is defined as the concentration of drug extrapolated to infinite time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Day 1 up to Day 31 | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. |
| Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | Day 1 up to Day 31 | — |
Countries
Germany, New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Germany, New Zealand, and United States. The first participant was screened on 03 April 2018. The last study visit occurred on 09 August 2018.
Pre-assignment details
38 participants were screened. Per protocol, participants in adaptive Cohort 2 (severe hepatic impairment) and Cohort 3 (mild hepatic impairment) were not enrolled following review of safety and pharmacokinetic (PK) data from participants in Cohort 1 (moderate hepatic impairment).
Participants by arm
| Arm | Count |
|---|---|
| Moderate Hepatic Impairment Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state. | 10 |
| Healthy Control Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Healthy Control | Total | Moderate Hepatic Impairment |
|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 5.3 | 61 years STANDARD_DEVIATION 6.1 | 61 years STANDARD_DEVIATION 6.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 20 Participants | 10 Participants |
| Region of Enrollment Germany | 2 Participants | 4 Participants | 2 Participants |
| Region of Enrollment New Zealand | 2 Participants | 4 Participants | 2 Participants |
| Region of Enrollment United States | 6 Participants | 12 Participants | 6 Participants |
| Sex: Female, Male Female | 7 Participants | 14 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 3 / 10 | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: AUClast of Filgotinib
AUClast is defined as the concentration of drug from time zero to the last observable concentration.
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1
Population: The PK Analysis Set included all enrolled participants who received at least 1 dose of filgotinib and had at least 1 nonmissing postdose concentration value of filgotinib or its primary metabolite GS-829845 reported by the PK laboratory.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | Pharmacokinetic (PK) Parameter: AUClast of Filgotinib | 2389.3 h*ng/mL | Standard Deviation 530.85 |
| Healthy Control | Pharmacokinetic (PK) Parameter: AUClast of Filgotinib | 1981.9 h*ng/mL | Standard Deviation 995.78 |
Comparison: An analysis of variance (ANOVA) model was fitted to the natural logarithmic transformed values of the AUClast. Two-sided 90% confidence intervals (CI) were calculated for the geometric least-squares mean (GLSM) ratio of AUClast between hepatic impairment group versus the matched control (normal hepatic function) group.90% CI: [80.77, 321.48]
Primary
PK Parameter: AUCinf of Filgotinib
AUCinf is defined as the concentration of drug extrapolated to infinite time.
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | PK Parameter: AUCinf of Filgotinib | 2417.0 h*ng/mL | Standard Deviation 533.74 |
| Healthy Control | PK Parameter: AUCinf of Filgotinib | 1995.9 h*ng/mL | Standard Deviation 997.88 |
Comparison: An ANOVA model was fitted to the natural logarithmic transformed values of the AUCinf. Two-sided 90% CI were calculated for the GLSM ratio of AUCinf between hepatic impairment group versus the matched control (normal hepatic function) group.90% CI: [82.22, 308.06]
Primary
PK Parameter: AUCinf of GS-829845
AUCinf is defined as the concentration of drug extrapolated to infinite time. GS-829845 is the primary metabolite of filgotinib.
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | PK Parameter: AUCinf of GS-829845 | 33296.5 h*ng/mL | Standard Deviation 11568.33 |
| Healthy Control | PK Parameter: AUCinf of GS-829845 | 32060.0 h*ng/mL | Standard Deviation 14329.57 |
Comparison: An ANOVA model was fitted to the natural logarithmic transformed values of the AUCinf. Two-sided 90% CI were calculated for the GLSM ratio of AUCinf between hepatic impairment group versus the matched control (normal hepatic function) group.90% CI: [69.9, 214.07]
Primary
PK Parameter: AUClast of GS-829845
AUClast is defined as the concentration of drug from time zero to the last observable concentration. GS-829845 is the primary metabolite of filgotinib.
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | PK Parameter: AUClast of GS-829845 | 32466.8 h*ng/mL | Standard Deviation 10898.85 |
| Healthy Control | PK Parameter: AUClast of GS-829845 | 31412.6 h*ng/mL | Standard Deviation 13758.34 |
Comparison: An ANOVA model was fitted to the natural logarithmic transformed values of the AUClast. Two-sided 90% CI were calculated for the GLSM ratio of AUClast between hepatic impairment group versus the matched control (normal hepatic function) group.90% CI: [69.67, 213.89]
Primary
PK Parameter: Cmax of Filgotinib
Cmax is defined as the maximum observed concentration of drug.
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | PK Parameter: Cmax of Filgotinib | 722.6 ng/mL | Standard Deviation 293.24 |
| Healthy Control | PK Parameter: Cmax of Filgotinib | 802.2 ng/mL | Standard Deviation 485.98 |
Comparison: An ANOVA model was fitted to the natural logarithmic transformed values of the Cmax. Two-sided 90% CI were calculated for the GLSM ratio of Cmax between hepatic impairment group versus the matched control (normal hepatic function) group.90% CI: [58.75, 228.98]
Primary
PK Parameter: Cmax of GS-829845
Cmax is defined as the maximum observed concentration of drug. GS-829845 is the primary metabolite of filgotinib.
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | PK Parameter: Cmax of GS-829845 | 972.5 ng/mL | Standard Deviation 256.09 |
| Healthy Control | PK Parameter: Cmax of GS-829845 | 1122.6 ng/mL | Standard Deviation 447.45 |
Comparison: An ANOVA model was fitted to the natural logarithmic transformed values of the Cmax. Two-sided 90% CI were calculated for the GLSM ratio of Cmax between hepatic impairment group versus the matched control (normal hepatic function) group.90% CI: [60.12, 175.98]
Secondary
Percentage of Participants Who Experienced Graded Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant.
Time frame: Day 1 up to Day 31
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Moderate Hepatic Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Laboratory Abnormality | 90.0 percentage of participants |
| Moderate Hepatic Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 60.0 percentage of participants |
| Healthy Control | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Laboratory Abnormality | 70.0 percentage of participants |
| Healthy Control | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 0.0 percentage of participants |
Secondary
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events
Time frame: Day 1 up to Day 31
Population: The Safety Analysis Set included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moderate Hepatic Impairment | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 30.0 percentage of participants |
| Healthy Control | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 10.0 percentage of participants |