Hepatitis B Virus
Conditions
Keywords
Severe Hepatic Impairment
Brief summary
The primary objective of this study is to evaluate the single-dose pharmacokinetics of tenofovir alafenamide (TAF) and its metabolite tenofovir (TFV) in participants with normal hepatic function and in participants with severe hepatic impairment.
Interventions
DRUGTAF
25 mg tablet administered orally
Sponsors
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: * Screening laboratory parameters within defined thresholds * Creatinine clearance must be ≥ 60 mL/min Key
Exclusion criteria
* Females who are pregnant or nursing or males who have a pregnant partner * Infection with hepatitis B virus (HBV) or HIV * History of clinically significant illness (including psychiatric or cardiac) or any other medical disorder that may interfere with participant treatment and/or adherence to the protocol NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter: AUCinf of Tenofovir Alafenamide (TAF), Its Metabolite Tenofovir (TFV) and Free (Unbound) TAF | Predose (≤5 minutes), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 12, 24, 36, 48, 60, 72, 96, 120, and 144 hours postdose on Day 1 | AUCinf is defined as the concentration of drug extrapolated to infinite time. |
| PK Parameter: Cmax of TAF, Its Metabolite TFV and Free (Unbound) TAF | Predose (≤5 minutes), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 12, 24, 36, 48, 60, 72, 96, 120, and 144 hours postdose on Day 1 | Cmax is defined as the maximum concentration of drug. |
| PK Parameter: AUClast of TAF, Its Metabolite TFV and Free (Unbound) TAF | Predose (≤5 minutes), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 12, 24, 36, 48, 60, 72, 96, 120, and 144 hours postdose on Day 1 | AUClast is defined as the concentration of drug from time zero to the last observable concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | Day 1 plus 30 days | TEAEs are events that meet one of the following criteria: any AEs with onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. |
| Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Day 1 plus 30 days | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. These were graded as Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening. The most severe graded abnormality from all tests was counted for each participant. |
Countries
Germany, New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Germany, New Zealand, and the United States. The first participant was screened on 22 December 2014. The last study visit occurred on 17 April 2015.
Pre-assignment details
28 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Severe Hepatic Impairment Group Participants with severe hepatic impairment received a single oral dose of TAF 25 mg on Day 1. | 10 |
| Matched Normal Hepatic Function Group Participants with normal hepatic function received a single oral dose of TAF 25 mg on Day 1. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Severe Hepatic Impairment Group | Total | Matched Normal Hepatic Function Group |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 7.3 | 56 years STANDARD_DEVIATION 8.2 | 55 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 13 Participants | 6 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 | 1 Participants | 1 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 | 19 Participants | 9 Participants |
| Region of Enrollment Germany | 1 participants | 4 participants | 3 participants |
| Region of Enrollment New Zealand | 2 participants | 4 participants | 2 participants |
| Region of Enrollment United States | 7 participants | 12 participants | 5 participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 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 | 4 / 10 | 3 / 10 |
| serious Total, serious adverse events | 1 / 10 | 0 / 10 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: AUCinf of Tenofovir Alafenamide (TAF), Its Metabolite Tenofovir (TFV) and Free (Unbound) TAF
AUCinf is defined as the concentration of drug extrapolated to infinite time.
Time frame: Predose (≤5 minutes), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 12, 24, 36, 48, 60, 72, 96, 120, and 144 hours postdose on Day 1
Population: Participants in the PK Analysis Set (consisted of all enrolled participants who received at least 1 dose of the study drug and had at least 1 non-missing PK concentration data for each respective analyte) with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Severe Hepatic Impairment Group | Pharmacokinetic (PK) Parameter: AUCinf of Tenofovir Alafenamide (TAF), Its Metabolite Tenofovir (TFV) and Free (Unbound) TAF | TAF | 120.6 h*ng/mL | Standard Deviation 33.96 |
| Severe Hepatic Impairment Group | Pharmacokinetic (PK) Parameter: AUCinf of Tenofovir Alafenamide (TAF), Its Metabolite Tenofovir (TFV) and Free (Unbound) TAF | TFV | 219.9 h*ng/mL | Standard Deviation 118.7 |
| Severe Hepatic Impairment Group | Pharmacokinetic (PK) Parameter: AUCinf of Tenofovir Alafenamide (TAF), Its Metabolite Tenofovir (TFV) and Free (Unbound) TAF | Free (unbound) TAF | 42.8 h*ng/mL | Standard Deviation 11.76 |
| Matched Normal Hepatic Function Group | Pharmacokinetic (PK) Parameter: AUCinf of Tenofovir Alafenamide (TAF), Its Metabolite Tenofovir (TFV) and Free (Unbound) TAF | TAF | 228.2 h*ng/mL | Standard Deviation 85.3 |
| Matched Normal Hepatic Function Group | Pharmacokinetic (PK) Parameter: AUCinf of Tenofovir Alafenamide (TAF), Its Metabolite Tenofovir (TFV) and Free (Unbound) TAF | TFV | 304.0 h*ng/mL | Standard Deviation 72.45 |
| Matched Normal Hepatic Function Group | Pharmacokinetic (PK) Parameter: AUCinf of Tenofovir Alafenamide (TAF), Its Metabolite Tenofovir (TFV) and Free (Unbound) TAF | Free (unbound) TAF | 46.5 h*ng/mL | Standard Deviation 17.78 |
Comparison: TAF: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [41.98, 69.56]
Comparison: TFV: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [42.9, 92.7]
Comparison: Free (unbound) TAF: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [72.48, 122.99]
Primary
PK Parameter: AUClast of TAF, Its Metabolite TFV and Free (Unbound) TAF
AUClast is defined as the concentration of drug from time zero to the last observable concentration.
Time frame: Predose (≤5 minutes), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 12, 24, 36, 48, 60, 72, 96, 120, and 144 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Severe Hepatic Impairment Group | PK Parameter: AUClast of TAF, Its Metabolite TFV and Free (Unbound) TAF | TAF | 113.1 h*ng/mL | Standard Deviation 30.85 |
| Severe Hepatic Impairment Group | PK Parameter: AUClast of TAF, Its Metabolite TFV and Free (Unbound) TAF | TFV | 184.2 h*ng/mL | Standard Deviation 99.86 |
| Severe Hepatic Impairment Group | PK Parameter: AUClast of TAF, Its Metabolite TFV and Free (Unbound) TAF | Free (unbound) TAF | 41.7 h*ng/mL | Standard Deviation 11.17 |
| Matched Normal Hepatic Function Group | PK Parameter: AUClast of TAF, Its Metabolite TFV and Free (Unbound) TAF | TAF | 225.7 h*ng/mL | Standard Deviation 85.09 |
| Matched Normal Hepatic Function Group | PK Parameter: AUClast of TAF, Its Metabolite TFV and Free (Unbound) TAF | TFV | 256.7 h*ng/mL | Standard Deviation 59.91 |
| Matched Normal Hepatic Function Group | PK Parameter: AUClast of TAF, Its Metabolite TFV and Free (Unbound) TAF | Free (unbound) TAF | 46 h*ng/mL | Standard Deviation 17.75 |
Comparison: TAF: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [40.11, 65.36]
Comparison: TFV: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [41.92, 91.82]
Comparison: Free (unbound) TAF: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [72.62, 119.8]
Primary
PK Parameter: Cmax of TAF, Its Metabolite TFV and Free (Unbound) TAF
Cmax is defined as the maximum concentration of drug.
Time frame: Predose (≤5 minutes), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 12, 24, 36, 48, 60, 72, 96, 120, and 144 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Severe Hepatic Impairment Group | PK Parameter: Cmax of TAF, Its Metabolite TFV and Free (Unbound) TAF | TAF | 79.6 ng/mL | Standard Deviation 39.31 |
| Severe Hepatic Impairment Group | PK Parameter: Cmax of TAF, Its Metabolite TFV and Free (Unbound) TAF | TFV | 7.5 ng/mL | Standard Deviation 3.95 |
| Severe Hepatic Impairment Group | PK Parameter: Cmax of TAF, Its Metabolite TFV and Free (Unbound) TAF | Free (unbound) TAF | 29.9 ng/mL | Standard Deviation 17.36 |
| Matched Normal Hepatic Function Group | PK Parameter: Cmax of TAF, Its Metabolite TFV and Free (Unbound) TAF | TAF | 176.0 ng/mL | Standard Deviation 79.77 |
| Matched Normal Hepatic Function Group | PK Parameter: Cmax of TAF, Its Metabolite TFV and Free (Unbound) TAF | TFV | 7.6 ng/mL | Standard Deviation 1.83 |
| Matched Normal Hepatic Function Group | PK Parameter: Cmax of TAF, Its Metabolite TFV and Free (Unbound) TAF | Free (unbound) TAF | 36.2 ng/mL | Standard Deviation 18.38 |
Comparison: TAF: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [31.66, 64.25]
Comparison: TFV: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [64.77, 124.72]
Comparison: Free (unbound) TAF: Severe Hepatic Impairment Group vs. Matched Normal Hepatic Function Group90% CI: [56.58, 119.31]
Secondary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
TEAEs are events that meet one of the following criteria: any AEs with onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug.
Time frame: Day 1 plus 30 days
Population: The Safety Analysis Set included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Severe Hepatic Impairment Group | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 40.0 percentage of participants |
| Matched Normal Hepatic Function Group | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 30.0 percentage of participants |
Secondary
Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. These were graded as Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening. The most severe graded abnormality from all tests was counted for each participant.
Time frame: Day 1 plus 30 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Severe Hepatic Impairment Group | Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Grade 1 | 40.0 percentage of participants |
| Severe Hepatic Impairment Group | Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Grade 2 | 40.0 percentage of participants |
| Severe Hepatic Impairment Group | Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Grade 3 | 20.0 percentage of participants |
| Severe Hepatic Impairment Group | Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Matched Normal Hepatic Function Group | Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Matched Normal Hepatic Function Group | Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Grade 1 | 30.0 percentage of participants |
| Matched Normal Hepatic Function Group | Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Grade 3 | 10.0 percentage of participants |
| Matched Normal Hepatic Function Group | Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Grade 2 | 30.0 percentage of participants |