Hepatic Insufficiency
Conditions
Keywords
hepatic impairment
Brief summary
This study will evaluate the effects of mild and moderate impairment of hepatic function on the single-dose pharmacokinetics, safety and tolerability of AG-013736.
Interventions
DRUGAG-013736
Single oral 5-mg dose of AG-013736, administered as a film-coated, immediate-release tablet.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Diagnosis of reduced hepatic function (Child Pugh Classification A or B) * Body Mass Index of 18-32 kg/m2
Exclusion criteria
* History of febrile illness within 5 days prior to first dose * Any condition possibly affecting drug absorption (e.g. gastrectomy) * Positive urine drug screen
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hours (hrs) post-dose | — |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Elimination Half-life (t1/2) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Plasma elimination half-life is the time measured for the plasma concentration to decrease by one half. |
| Apparent Oral Clearance (CL/F) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Apparent Volume of Distribution (Vz/F) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the oral bioavailability. |
| Fraction of Unbound Drug (fu) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). |
| Unbound Apparent Volume of Distribution (Vzu/F) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Volume of distribution of unbound drug is defined as the theoretical volume in which the total amount of unbound drug would need to be uniformly distributed to produce the desired plasma concentration of unbound drug. Unbound apparent volume of distribution after oral dose (Vzu/F) is influenced by the oral bioavailability. |
| Unbound Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)u] | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | AUC (0 - ∞)u = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞) for unbound drug. It is obtained from AUCu (0 - t) plus AUCu (t - ∞). |
| Unbound Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClastu) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClastu) for unbound drug. |
| Unbound Maximum Observed Plasma Concentration (Cmaxu) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Cmaxu is the highest measured unbound plasma concentration during the dosing interval. |
| Unbound Apparent Oral Clearance (CLu/F) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | Clearance of an unbound drug is a measure of the rate at which an unbound drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability. Unbound drug clearance is a quantitative measure of the rate at which an unbound drug substance is removed from the blood. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Axitinib : Normal Hepatic Function Single oral dose of axitinib (AG-013736) 5 milligrams (mg) immediate release tablets (IRT) on Day 1 to participants with normal hepatic function. | 8 |
| Axitinib : Mild Hepatic Impairment Single oral dose of axitinib (AG-013736) 5 mg IRT on Day 1 to participants with mild hepatic impairment. Mild hepatic impairment (grade A) is defined as a Child-Pugh (CP) total score of 5-6. The CP classification assesses 5 hepatic parameters (total serum bilirubin, serum albumin, prothrombin time or prothrombin time international normalized ratio \[INR\], ascites and encephalopathy grade) on a scale of 1 (mild or none) to 3 (most severe). Total mild hepatic impairment score range is 5 (mild) to 15 (severe). | 8 |
| Axitinib : Moderate Hepatic Impairment Single oral dose of axitinib (AG-013736) 5 mg IRT on Day 1 to participants with moderate hepatic impairment. Moderate hepatic impairment (grade B) is defined as a CP total score of 7-9. The CP classification assesses 5 hepatic parameters (total serum bilirubin, serum albumin, prothrombin time or prothrombin time INR, ascites and encephalopathy grade) on a scale of 1 (mild or none) to 3 (most severe). Total moderate hepatic impairment score range is 5 (mild) to 15 (severe). | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Axitinib : Normal Hepatic Function | Axitinib : Mild Hepatic Impairment | Axitinib : Moderate Hepatic Impairment | Total |
|---|---|---|---|---|
| Age Continuous | 47.4 years STANDARD_DEVIATION 5.2 | 52.5 years STANDARD_DEVIATION 5.6 | 54.3 years STANDARD_DEVIATION 4.7 | 51.4 years STANDARD_DEVIATION 5.8 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 6 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 | 3 / 8 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)]
AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 155.68 ng*hr/mL | Geometric Coefficient of Variation 63 |
| Axitinib : Mild Hepatic Impairment | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 121.96 ng*hr/mL | Geometric Coefficient of Variation 167 |
| Axitinib : Moderate Hepatic Impairment | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 303.96 ng*hr/mL | Geometric Coefficient of Variation 44 |
Comparison: For mild hepatic impairment, ANOVA was used to compare natural log transformed AUC (0 - ∞) of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [39.92, 153.75]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed AUC (0 - ∞) of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [99.49, 383.18]
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hours (hrs) post-dose
Population: Pharmacokinetic (PK) concentration population included all participants who were treated and had at least 1 concentration measurement.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Maximum Observed Plasma Concentration (Cmax) | 30.43 ng/mL | Geometric Coefficient of Variation 50 |
| Axitinib : Mild Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) | 26.96 ng/mL | Geometric Coefficient of Variation 127 |
| Axitinib : Moderate Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) | 38.85 ng/mL | Geometric Coefficient of Variation 50 |
Comparison: For mild hepatic impairment, analysis of variance (ANOVA) was used to compare natural log transformed Cmax of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and confidence intervals (CIs) on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [49.2, 159.56]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed Cmax of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [70.9, 229.91]
Secondary
Apparent Oral Clearance (CL/F)
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Apparent Oral Clearance (CL/F) | 535.3 mL/min | Geometric Coefficient of Variation 63 |
| Axitinib : Mild Hepatic Impairment | Apparent Oral Clearance (CL/F) | 683.3 mL/min | Geometric Coefficient of Variation 167 |
| Axitinib : Moderate Hepatic Impairment | Apparent Oral Clearance (CL/F) | 274.2 mL/min | Geometric Coefficient of Variation 44 |
Secondary
Apparent Volume of Distribution (Vz/F)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the oral bioavailability.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Apparent Volume of Distribution (Vz/F) | 166.43 Liter (L) | Geometric Coefficient of Variation 52 |
| Axitinib : Mild Hepatic Impairment | Apparent Volume of Distribution (Vz/F) | 162.65 Liter (L) | Geometric Coefficient of Variation 87 |
| Axitinib : Moderate Hepatic Impairment | Apparent Volume of Distribution (Vz/F) | 127.68 Liter (L) | Geometric Coefficient of Variation 67 |
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 148.43 ng*hr/mL | Geometric Coefficient of Variation 69 |
| Axitinib : Mild Hepatic Impairment | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 115.98 ng*hr/mL | Geometric Coefficient of Variation 180 |
| Axitinib : Moderate Hepatic Impairment | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 295.23 ng*hr/mL | Geometric Coefficient of Variation 44 |
Comparison: For mild hepatic impairment, ANOVA was used to compare natural log transformed AUClast of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [38.68, 157.82]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed AUClast of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [98.47, 401.74]
Secondary
Fraction of Unbound Drug (fu)
Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure for each group respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Fraction of Unbound Drug (fu) | 0.004 Ratio | Geometric Coefficient of Variation 25 |
| Axitinib : Mild Hepatic Impairment | Fraction of Unbound Drug (fu) | 0.003 Ratio | Geometric Coefficient of Variation 50 |
| Axitinib : Moderate Hepatic Impairment | Fraction of Unbound Drug (fu) | 0.004 Ratio | Geometric Coefficient of Variation 134 |
Comparison: For mild hepatic impairment, ANOVA was used to compare natural log transformed fu of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [37.4, 145.56]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed fu of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [55.58, 183.02]
Secondary
Plasma Elimination Half-life (t1/2)
Plasma elimination half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Plasma Elimination Half-life (t1/2) | 4.74 hr | Standard Deviation 3.77 |
| Axitinib : Mild Hepatic Impairment | Plasma Elimination Half-life (t1/2) | 3.61 hr | Standard Deviation 3.02 |
| Axitinib : Moderate Hepatic Impairment | Plasma Elimination Half-life (t1/2) | 7.12 hr | Standard Deviation 6.49 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Axitinib : Normal Hepatic Function | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 3.50 hr |
| Axitinib : Mild Hepatic Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 2.75 hr |
| Axitinib : Moderate Hepatic Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 4.00 hr |
Secondary
Unbound Apparent Oral Clearance (CLu/F)
Clearance of an unbound drug is a measure of the rate at which an unbound drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability. Unbound drug clearance is a quantitative measure of the rate at which an unbound drug substance is removed from the blood.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure for each group respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Unbound Apparent Oral Clearance (CLu/F) | 132218.6 mL/min | Geometric Coefficient of Variation 56 |
| Axitinib : Mild Hepatic Impairment | Unbound Apparent Oral Clearance (CLu/F) | 120883.5 mL/min | Geometric Coefficient of Variation 82 |
| Axitinib : Moderate Hepatic Impairment | Unbound Apparent Oral Clearance (CLu/F) | 67143.1 mL/min | Geometric Coefficient of Variation 109 |
Comparison: For mild hepatic impairment, ANOVA was used to compare natural log transformed CLu/F of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [44.75, 186.79]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed CLu/F of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [27.14, 95.03]
Secondary
Unbound Apparent Volume of Distribution (Vzu/F)
Volume of distribution of unbound drug is defined as the theoretical volume in which the total amount of unbound drug would need to be uniformly distributed to produce the desired plasma concentration of unbound drug. Unbound apparent volume of distribution after oral dose (Vzu/F) is influenced by the oral bioavailability.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure for each group respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Unbound Apparent Volume of Distribution (Vzu/F) | 41108.6 L | Geometric Coefficient of Variation 57 |
| Axitinib : Mild Hepatic Impairment | Unbound Apparent Volume of Distribution (Vzu/F) | 42378.3 L | Geometric Coefficient of Variation 40 |
| Axitinib : Moderate Hepatic Impairment | Unbound Apparent Volume of Distribution (Vzu/F) | 31268.8 L | Geometric Coefficient of Variation 121 |
Comparison: For mild hepatic impairment, ANOVA was used to compare natural log transformed Vzu/F of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [51.53, 206.22]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed Vzu/F of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [41.41, 139.73]
Secondary
Unbound Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)u]
AUC (0 - ∞)u = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞) for unbound drug. It is obtained from AUCu (0 - t) plus AUCu (t - ∞).
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure for each group respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Unbound Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)u] | 0.63 ng*hr/mL | Geometric Coefficient of Variation 56 |
| Axitinib : Mild Hepatic Impairment | Unbound Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)u] | 0.69 ng*hr/mL | Geometric Coefficient of Variation 82 |
| Axitinib : Moderate Hepatic Impairment | Unbound Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)u] | 1.24 ng*hr/mL | Geometric Coefficient of Variation 109 |
Comparison: For mild hepatic impairment, ANOVA was used to compare natural log transformed AUC (0 - ∞)u of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [53.54, 223.47]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed AUC (0 - ∞)u of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [105.23, 368.49]
Secondary
Unbound Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClastu)
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClastu) for unbound drug.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK parameter analysis population included all participants who were treated and had at least 1 of the PK parameters of interest. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure for each group respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Unbound Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClastu) | 0.60 ng*hr/mL | Geometric Coefficient of Variation 61 |
| Axitinib : Mild Hepatic Impairment | Unbound Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClastu) | 0.67 ng*hr/mL | Geometric Coefficient of Variation 81 |
| Axitinib : Moderate Hepatic Impairment | Unbound Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClastu) | 1.21 ng*hr/mL | Geometric Coefficient of Variation 106 |
Comparison: For mild hepatic impairment, ANOVA was used to compare natural log transformed AUClastu of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [54.35, 229.37]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed AUClastu of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [106.68, 377.2]
Secondary
Unbound Maximum Observed Plasma Concentration (Cmaxu)
Cmaxu is the highest measured unbound plasma concentration during the dosing interval.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 16, 24, 36, 48, 96 and 144 hrs post-dose
Population: PK concentration population included all participants who were treated and had at least 1 concentration measurement. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure for each group respectively.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Axitinib : Normal Hepatic Function | Unbound Maximum Observed Plasma Concentration (Cmaxu) | 0.12 ng/mL | Geometric Coefficient of Variation 46 |
| Axitinib : Mild Hepatic Impairment | Unbound Maximum Observed Plasma Concentration (Cmaxu) | 0.13 ng/mL | Geometric Coefficient of Variation 47 |
| Axitinib : Moderate Hepatic Impairment | Unbound Maximum Observed Plasma Concentration (Cmaxu) | 0.16 ng/mL | Geometric Coefficient of Variation 97 |
Comparison: For mild hepatic impairment, ANOVA was used to compare natural log transformed Cmaxu of axitinib (AG-013736) between the control group (normal hepatic function) and mild hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (mild hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [58.22, 195.99]
Comparison: For moderate hepatic impairment, ANOVA was used to compare natural log transformed Cmaxu of axitinib (AG-013736) between the control group (normal hepatic function) and moderate hepatic impairment. The point estimates and CIs on the log-scale were back transformed to provide estimates of the ratio of adjusted geometric means (moderate hepatic impairment/normal hepatic function) and 90% CIs for the ratios.90% CI: [75.62, 219.25]