Renal Insufficiency
Conditions
Keywords
Subjects with Renal Impairment, healthy
Brief summary
Patients with renal impairment are the target population for PF-04634817. The clearance mechanism of this drug means that exposure may be increased in subjects with renal impairment. This study will investigate the effect of the drug in subjects with varying degrees of renal impairment. Pharmacokinetics, safety and toleration will be assessed.
Interventions
DRUGPF-04634817
Single 50 mg dose administered to subjects with normal renal function (creatinine clearance greater than or equal to 90 ml/min)
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female (non child bearing potential aged 18-75 years * Documented renal impairment (mild, moderate or severe using Cockcroft-Gault equation) or matched healthy volunteers (age, weight and gender)
Exclusion criteria
* Subjects with acute renal failure * Subjects receiving, or likely to receive, CYP450 3A4 inhibitors * Abnormal ECG at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Decay Half-Life (t1/2) | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Maximum Observed Plasma Concentration (Cmax) | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose | — |
| Apparent Volume of Distribution (Vz/F) | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours 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 fraction absorbed. |
| Area Under the Curve From Time Zero to 48 Hours[AUC (0 - 48)] | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose | AUC (0 - 48)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to 48hours. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose | AUC (0 - inf)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time. |
| Apparent Oral Clearance (CL/F) | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours 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 fraction of the dose absorbed. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of the Dose Excreted Unchanged in the Urine Over 48 Hours (Ae48%) | 0-24, 24-48 post dose | Percentage (%) of drug excreted unchanged in urine over 48 hours (Ae48%) = Ae48/(dose x 100). |
| Renal Clearance Over a 48-hour Interval(CLr48) | 0-24, 24-48 hours post dose | Renal clearance over a 48-hour interval (CLr48) = Ae48/AUC48. |
| Amount of Unchanged Drug Excreted in Urine Over 48 Hours (Ae48) | 0-24, 24-48 hours post dose | Amount of unchanged drug excreted in urine over 48 hours (Ae48) = urine concentration x volume of urine. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Normal Renal Function An oral dose of PF-04634817 50 milligram (mg) was administered to participants with normal renal function (defined as a creatinine clearance \[CrCL\] of more than or equal \[\>=\] to 90 milligrams \[mL\]/minute \[min\], estimated using the Cockcroft-Gault Equation). | 8 |
| Mild Renal Impairment An oral dose of PF-04634817 50 mg was administered to participants with mild renal impairment (defined as a CrCL of 60 to 89 mL/min, estimated using the Cockcroft-Gault Equation). | 8 |
| Moderate Renal Impairment An oral dose of PF-04634817 50 mg was administered to participants with moderate renal impairment (defined as a CrCL of 30 to 59 mL/min, estimated using the Cockcroft-Gault Equation). | 8 |
| Severe Renal Impairment An oral dose of PF-04634817 50 mg was administered to participants with severe renal impairment (defined as a CrCL of 15 to 29 mL/min, estimated using the Cockcroft-Gault Equation). | 7 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Randomized, not treated | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Normal Renal Function | Mild Renal Impairment | Moderate Renal Impairment | Severe Renal Impairment | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60.0 Years STANDARD_DEVIATION 5.2 | 66.5 Years STANDARD_DEVIATION 3.9 | 61.9 Years STANDARD_DEVIATION 3.2 | 59.0 Years STANDARD_DEVIATION 12 | 61.9 Years STANDARD_DEVIATION 7.5 |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 2 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 6 Participants | 4 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 3 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 1 / 7 |
Outcome results
Primary
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 fraction of the dose absorbed. 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: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. N = the number of participants with reportable CL/F values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Apparent Oral Clearance (CL/F) | 565.8 milliliter/minute (mL/min) | Geometric Coefficient of Variation 29 |
| Mild Renal Impairment | Apparent Oral Clearance (CL/F) | 526.8 milliliter/minute (mL/min) | Geometric Coefficient of Variation 44 |
| Moderate Renal Impairment | Apparent Oral Clearance (CL/F) | 319.2 milliliter/minute (mL/min) | Geometric Coefficient of Variation 45 |
| Severe Renal Impairment | Apparent Oral Clearance (CL/F) | 215.2 milliliter/minute (mL/min) | Geometric Coefficient of Variation 37 |
Primary
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 fraction absorbed.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. N = the number of participants with reportable Vz/F values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Apparent Volume of Distribution (Vz/F) | 1453 Liter (L) | Geometric Coefficient of Variation 35 |
| Mild Renal Impairment | Apparent Volume of Distribution (Vz/F) | 1808 Liter (L) | Geometric Coefficient of Variation 38 |
| Moderate Renal Impairment | Apparent Volume of Distribution (Vz/F) | 1162 Liter (L) | Geometric Coefficient of Variation 57 |
| Severe Renal Impairment | Apparent Volume of Distribution (Vz/F) | 742.3 Liter (L) | Geometric Coefficient of Variation 53 |
Primary
Area Under the Curve From Time Zero to 48 Hours[AUC (0 - 48)]
AUC (0 - 48)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to 48hours.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose
Population: The pharmacokinetics (PK) parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Curve From Time Zero to 48 Hours[AUC (0 - 48)] | 1294 Nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 27 |
| Mild Renal Impairment | Area Under the Curve From Time Zero to 48 Hours[AUC (0 - 48)] | 1399 Nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 42 |
| Moderate Renal Impairment | Area Under the Curve From Time Zero to 48 Hours[AUC (0 - 48)] | 2024 Nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 35 |
| Severe Renal Impairment | Area Under the Curve From Time Zero to 48 Hours[AUC (0 - 48)] | 2860 Nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 34 |
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)]
AUC (0 - inf)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. N = number of participants with reportable AUC(0-inf) values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 1473 ng*h/mL | Geometric Coefficient of Variation 29 |
| Mild Renal Impairment | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 1584 ng*h/mL | Geometric Coefficient of Variation 44 |
| Moderate Renal Impairment | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 2611 ng*h/mL | Geometric Coefficient of Variation 45 |
| Severe Renal Impairment | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 3877 ng*h/mL | Geometric Coefficient of Variation 37 |
Primary
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: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 1467 ng*h/mL | Geometric Coefficient of Variation 29 |
| Mild Renal Impairment | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 1575 ng*h/mL | Geometric Coefficient of Variation 44 |
| Moderate Renal Impairment | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 2610 ng*h/mL | Geometric Coefficient of Variation 42 |
| Severe Renal Impairment | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 3845 ng*h/mL | Geometric Coefficient of Variation 37 |
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Maximum Observed Plasma Concentration (Cmax) | 124.6 ng/mL | Geometric Coefficient of Variation 49 |
| Mild Renal Impairment | Maximum Observed Plasma Concentration (Cmax) | 111.4 ng/mL | Geometric Coefficient of Variation 66 |
| Moderate Renal Impairment | Maximum Observed Plasma Concentration (Cmax) | 123.7 ng/mL | Geometric Coefficient of Variation 59 |
| Severe Renal Impairment | Maximum Observed Plasma Concentration (Cmax) | 132.3 ng/mL | Geometric Coefficient of Variation 59 |
Primary
Plasma Decay Half-Life (t1/2)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. N = the number of participants with reportable t1/2 values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Plasma Decay Half-Life (t1/2) | 31.01 hours | Standard Deviation 11.33 |
| Mild Renal Impairment | Plasma Decay Half-Life (t1/2) | 43.94 hours | Standard Deviation 24.4 |
| Moderate Renal Impairment | Plasma Decay Half-Life (t1/2) | 43.57 hours | Standard Deviation 11.89 |
| Severe Renal Impairment | Plasma Decay Half-Life (t1/2) | 44.94 hours | Standard Deviation 23.96 |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, 84, 96, 108, 120, 132, 144, 156, 216, 312 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 2.01 hours |
| Mild Renal Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 2.50 hours |
| Moderate Renal Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 2.00 hours |
| Severe Renal Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 3.00 hours |
Secondary
Amount of Unchanged Drug Excreted in Urine Over 48 Hours (Ae48)
Amount of unchanged drug excreted in urine over 48 hours (Ae48) = urine concentration x volume of urine.
Time frame: 0-24, 24-48 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Amount of Unchanged Drug Excreted in Urine Over 48 Hours (Ae48) | 9303000 ng | Geometric Coefficient of Variation 48 |
| Mild Renal Impairment | Amount of Unchanged Drug Excreted in Urine Over 48 Hours (Ae48) | 5993000 ng | Geometric Coefficient of Variation 47 |
| Moderate Renal Impairment | Amount of Unchanged Drug Excreted in Urine Over 48 Hours (Ae48) | 4997000 ng | Geometric Coefficient of Variation 26 |
| Severe Renal Impairment | Amount of Unchanged Drug Excreted in Urine Over 48 Hours (Ae48) | 3097000 ng | Geometric Coefficient of Variation 65 |
Secondary
Percentage of the Dose Excreted Unchanged in the Urine Over 48 Hours (Ae48%)
Percentage (%) of drug excreted unchanged in urine over 48 hours (Ae48%) = Ae48/(dose x 100).
Time frame: 0-24, 24-48 post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. Note that the measure of dispersion should be simply coefficient of variation (CV) instead of geometric CV (GCV) for Ae48%. GCV was chosen due to absence of CV in the options given for that field.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Percentage of the Dose Excreted Unchanged in the Urine Over 48 Hours (Ae48%) | 18.61 percentage of unchanged drug excreted | Geometric Coefficient of Variation 44 |
| Mild Renal Impairment | Percentage of the Dose Excreted Unchanged in the Urine Over 48 Hours (Ae48%) | 12.00 percentage of unchanged drug excreted | Geometric Coefficient of Variation 43 |
| Moderate Renal Impairment | Percentage of the Dose Excreted Unchanged in the Urine Over 48 Hours (Ae48%) | 9.989 percentage of unchanged drug excreted | Geometric Coefficient of Variation 25 |
| Severe Renal Impairment | Percentage of the Dose Excreted Unchanged in the Urine Over 48 Hours (Ae48%) | 6.193 percentage of unchanged drug excreted | Geometric Coefficient of Variation 62 |
Secondary
Renal Clearance Over a 48-hour Interval(CLr48)
Renal clearance over a 48-hour interval (CLr48) = Ae48/AUC48.
Time frame: 0-24, 24-48 hours post dose
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Renal Clearance Over a 48-hour Interval(CLr48) | 119.8 mL/min | Geometric Coefficient of Variation 39 |
| Mild Renal Impairment | Renal Clearance Over a 48-hour Interval(CLr48) | 71.40 mL/min | Geometric Coefficient of Variation 41 |
| Moderate Renal Impairment | Renal Clearance Over a 48-hour Interval(CLr48) | 41.13 mL/min | Geometric Coefficient of Variation 36 |
| Severe Renal Impairment | Renal Clearance Over a 48-hour Interval(CLr48) | 18.05 mL/min | Geometric Coefficient of Variation 59 |