Roxadustat (FG-4592/ASP1517) ISN 1517-CL-0543Renal AnemiaCONFIDENTIAL EudraCT number 2015-002565-28
Name of Sponsor/Company:Astellas Pharma Global Development, Inc.
Name of Finished Product:Roxadustat (FG-4592/ASP1517)
Name of Active Ingredient:Roxadustat (FG-4592/ASP1517)
Aug 2018 Astellas Synopsis Page 1 of 30
SYNOPSIS
Title of Study:
A Phase 1 Study to Evaluate the Pharmacokinetics of Roxadustat in Subjects with Different Degrees of Renal
Function (1517-CL-0543)
Investigators/Coordinating Investigator:
, MD (Site Number ) and (Site Number )
Study Center(s):
UK (Site Number ) and , Germany (Site Number )
Publication Based on the Study:
Not applicable
Study Period:
4Q2016 to 4Q2017
Study Initiation Date (Date of First Evaluation):
12 Dec 2016
Study Completion Date (Date of Last Evaluation):
11 Dec 2017
Phase of Development:
Phase 1
Objectives:
Primary Objectives
Subjects with Normal Renal Function or Severely Impaired Renal Function
● To evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma and urine
Subjects with End-stage Renal Disease on Continuous Ambulatory Peritoneal Dialysis or Automated Peritoneal
Dialysis
● To evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma, urine and dialysate
Roxadustat (FG-4592/ASP1517) ISN 1517-CL-0543Renal AnemiaCONFIDENTIAL EudraCT number 2015-002565-28
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Subjects with End-stage Renal Disease on Hemodialysis or Hemodiafiltration
● To evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma, urine and dialysate
● To evaluate the effect of dialysis on the pharmacokinetics of roxadustat and its main metabolites
Secondary Objectives
● To evaluate the safety and tolerability of roxadustat
● To evaluate the pharmacodynamics of roxadustat
Exploratory Objective
● To compare the pharmacokinetics of roxadustat and its main metabolites in subjects with severely
impaired renal function or end-stage renal disease (ESRD) relative to the pharmacokinetics of roxadustat
in subjects with normal renal function
Methodology:
This study was a phase 1 study to investigate the pharmacokinetics, metabolic profile, pharmacodynamics,
safety and tolerability of a single dose of roxadustat in subjects with severely impaired renal function or ESRD.
The pharmacokinetics, metabolic profile, pharmacodynamics, safety and tolerability of a single dose of
roxadustat were also investigated in subjects with normal renal function and the results compared to subjects
with severely impaired renal function or ESRD.
Subjects with Normal Renal Function or Severely Impaired Renal Function and Subjects with End-stage Renal
Disease on Continuous Ambulatory Peritoneal Dialysis or Automated Peritoneal Dialysis
Screening took place from days -30 to -3 and the subjects were admitted to the clinical unit on day -2. The
treatment period lasted 8 days, during which the subjects received a single oral dose of 100 mg roxadustat in the
morning of day 1.
Pharmacokinetics of roxadustat and its main metabolites (O-glucuronide-, O-glucoside- and sulphate of
hydroxy-roxadustat) in plasma, urine and dialysate were assessed. In addition, plasma protein binding of
roxadustat was assessed on day 1.
Subjects completed the treatment period on day 6, provided that all required assessments had been performed
and there were no medical reasons for a prolonged follow-up. The study was completed with an end-of-study
visit (ESV), which took place between 5 and 9 days after the last treatment period-defined assessment (or after
early withdrawal).
Subjects with End-stage Renal Disease on Hemodialysis or Hemodiafiltration
A 2-period, single-sequence design was used for subjects with ESRD on hemodialysis (HD) or
hemodiafiltration (HDF). Screening took place from days -30 to -3 and the subjects completed 2 treatment
periods in order to evaluate the pharmacokinetics of roxadustat with dosing after and before dialysis:
● In treatment period 1, subjects were admitted to the clinical unit on the day of the first dialysis session of
the week (e.g., Mon if subject was on a Mon-Wed-Fri-regimen or Tue if subject was on a
Tue-Thu-Sat-regimen) (day -2). The subjects received a single oral dose of 100 mg roxadustat 2 hours
after completion of hemodialysis on day 1 of treatment period 1.
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● In treatment period 2, subjects were admitted to the clinical unit the day before the second dialysis session
of the week (e.g., Tue if subject was on a Mon-Wed-Fri regimen or Wed if subject was on a
Tue-Thu-Sat-regimen) (day -1). The subjects received a single oral dose of 100 mg roxadustat 2 hours
prior to the start of hemodialysis on day 1 of treatment period 2.
The washout between treatment periods 1 and 2 was minimally 1 week and maximally 3 weeks, between day 6
of treatment period 1 and day -1 of treatment period 2.
In both treatment periods the pharmacokinetics of roxadustat and its main metabolites (O-glucuronide-,
O-glucoside- and sulphate of hydroxy-roxadustat) in plasma and urine (for all subjects with residual urine
production) were assessed. The pharmacokinetics of roxadustat and its main metabolites (O-glucuronide-,
O-glucoside- and sulphate of hydroxy-roxadustat) in dialysate was assessed in treatment period 2 only. In
addition, plasma protein binding of roxadustat was assessed on day 1 of treatment periods 1 and 2.
Subjects completed the treatment period on day 6 of treatment period 2, provided that all required assessments
had been performed and there were no medical reasons for a prolonged follow-up. The study was completed
with an ESV, which took place between 5 and 9 days after the last treatment period 2-defined assessment (or
after early withdrawal).
HD and HDF subjects could have used low flux and high flux dialysis filters.
All Subjects
Erythropoietin (EPO) was not assessed for subjects who were on treatment with long-acting
erythropoiesis-stimulating agents (ESAs) (i.e., darbepoetin and MPG-EPO) at that time. Continuous heart rate
measurement was performed for 24 hours prior to dosing (after completion of dialysis on day -2 in HD/HDF
subjects) and for 24 hours after dosing (only in treatment period 1 in HD/HDF subjects). An optional
biobanking sample may have been taken for potential exploratory, retrospective, gene polymorphism analysis.
Roxadustat plasma, urine and dialysate samples were stored for potential exploratory metabolic profiling or
exploratory biomarker analysis after the study.
Number of Patients (Planned, Enrolled and Analyzed):
A sufficient number of subjects were enrolled to evaluate the pharmacokinetics of roxadustat and its main
metabolites in subjects with different degrees of renal function in this exploratory clinical pharmacokinetic
study.
The remaining 34 (46.6%) subjects were enrolled (registered) into the study and received roxadustat. Only 1 of
these subjects was in the ESRD on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal
dialysis (APD) renal function group. The recruitment of the full number of required subjects for the ESRD on
CAPD or APD renal function group was difficult and not possible within the given time frame.
Of the 34 enrolled subjects, 28 subjects were enrolled at the site in Germany and 6 subjects were enrolled at the
site in the UK
All registered subjects completed the study as per the protocol. All registered subjects that received roxadustat
were included in the safety, pharmacokinetic and pharmacodynamics analysis sets.
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Diagnosis and Main Criteria for Inclusion:
Male or female subjects with a body weight within the range of 45 to 160 kg (inclusive [screening]), who
provided written informed consent and to whom all of the inclusion and none of the exclusion criteria applied
were eligible for inclusion in this study.
If a subject with impaired renal function was being treated with short acting ESAs, the subject had to agree to
discontinue treatment for at least 14 days prior to admission.
Subjects who had any condition which, in the investigator’s opinion, made the subject unsuitable for clinical
study participation were excluded from the study.
Specific Inclusion Criteria for Subjects with Normal Renal Function
Subject was aged 40 to 75 years (inclusive [screening]) and had a predose estimated glomerular filtration rate
(eGFR) value based on the Modification of Diet in Renal Disease (MDRD) method (screening) of ≥ 90 mL/min
per 1.73 m2.
Specific Inclusion Criteria for Subjects with Severely Impaired Renal Function
Subject was aged 18 to 75 years (inclusive [screening]), had a predose eGFR value based on the abbreviated
MDRD method (screening) of < 30 mL/min/1.73 m2 and was not on dialysis.
Specific Inclusion Criteria for Subjects with End-stage Renal Disease on Continuous Ambulatory Peritoneal
Dialysis or Automated Peritoneal Dialysis
Subject was aged 18 to 75 years (inclusive [screening]) and was on CAPD or APD treatment with the same
mode of dialysis for at least 4 months prior to admission to the clinical unit.
Specific Inclusion Criteria for Subjects with End-stage Renal Disease on Hemodialysis or Hemodiafiltration
Subject was aged 18 to 75 years (inclusive [screening]), was on HD or HDF treatment with the same mode of
dialysis for at least 4 months prior to admission to the clinical unit and should have had dialysis sessions 3 times
weekly.
Specific Exclusion Criteria for Subjects with Normal Renal Function
Subject used any prescribed or nonprescribed drugs within 2 weeks (or 5 half-lives, whichever was longer) prior
to admission to the clinical unit, except for occasional use of paracetamol (up to 2 g per day) and oral
contraceptives or hormone replacement therapy.
Specific Exclusion Criteria for Subjects with Impaired Renal Function (Including Severely Impaired Renal
Function and End-stage Renal Disease)
Subject had used immunosuppressant drugs or drugs used to treat malignancies (including corticosteroids at
doses > 10 mg prednisolone per day or equivalent) within 3 months prior to admission to the clinical unit.
Subject had an anticipated use of the following prohibited medication during the treatment and/or follow-up of
the study:
● Oral multivalent cation-containing drugs and mineral supplements, anion-exchange resins, sucralfate or
magnesium- or aluminium-containing antacids, phosphate binders and iron-chelating agents were not
allowed from 24 hours before until 48 hours after dosing.
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● Short-acting intravenous or subcutaneous ESA were not allowed within 2 weeks prior to admission to the
clinical unit until the ESV.
● Dapsone in any dose amount or anticipated chronic use of paracetamol > 2 g per day or nonsteroidal
anti-inflammatory drugs, except for low dose aspirin/acetylsalicylic acid, were not allowed from admission
to the clinical unit until the ESV.
Subject had not been on a stable dose of concomitant medication to treat concurrent chronic conditions for at
least 2 weeks (or 5 half-lives of the drug, whichever was longer) prior to admission to the clinical unit (minor
dose changes were allowed in agreement with the sponsor). Doses of statins should not have exceeded the
capped maximum daily doses at admission to the clinical unit. Rosuvastatin use was not allowed.
Subject had used any nonessential prescribed and nonprescribed drugs within 2 weeks (or 5 half-lives,
whichever was longer) prior to admission to the clinical unit.
Test Product, Dose and Mode of Administration, Batch Numbers:
Roxdustat was provided as 100 mg tablets (lot number: and expiry/re-evaluation date: 31 Aug 2018).
A single dose of 100 mg roxadustat was administered orally on day 1 under the following conditions:
Subjects with Normal Renal Function or Severely Impaired Renal Function
On the day of dosing the subject started with a breakfast (completed within 30 minutes), after which the subjects
refrained from water and food intake until dosing. Approximately 2.5 hours after completion of the breakfast
the roxadustat tablet was taken with 150 mL of water. After dosing the subject refrained from water and food
intake for at least 2 hours. Lunch may have been provided at any time after the fasting period.
Subjects with End-stage Renal Disease on Continuous Ambulatory Peritoneal Dialysis or Automated Peritoneal
Dialysis
Dosing of roxadustat took place after the first dwelling cycle of the day and before the second dwelling cycle.
Breakfast was served approximately 3 hours before dosing and needed to be completed within 30 minutes, after
which the subjects refrained from water and food intake until dosing. The roxadustat tablet was taken with
150 mL of water. After dosing, the subject refrained from water and food intake for at least 2 hours. Lunch
may have been provided at any time after the fasting period and dialysis procedures were to be taken into
consideration. Prior to a dwelling period, the dialysate was drained for approximately 20 minutes and dialysis
fluid was infused for approximately 10 minutes.
Subjects with End-stage Renal Disease on Hemodialysis or Hemodiafiltration
Treatment Period 1
On the day of dosing the subject started with a breakfast (completed within 30 minutes). Dialysis was initiated
approximately 1 hour after completion of the breakfast.
Lunch was provided during the dialysis session (completed within 30 minutes), after which subjects refrained
from water and food intake until dosing. Approximately 2 hours after completion of dialysis, the roxadustat
tablet was taken with 150 mL of water. After dosing, the subject refrained from water and food intake for at
least 2 hours. Dinner may have been provided at any time after the fasting period.
Roxadustat (FG-4592/ASP1517) ISN 1517-CL-0543Renal AnemiaCONFIDENTIAL EudraCT number 2015-002565-28
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Treatment Period 2
On the day of dosing the subject started with a breakfast (completed within 30 minutes), after which the subjects
refrained from water and food intake until dosing. Approximately 2.5 hours after completion of the breakfast
the roxadustat tablet was taken with 150 mL of water. After dosing, the subject refrained from water and food
intake for 2 hours. Dialysis was initiated approximately 2 hours after study drug intake. Lunch was provided
during the dialysis session.
Duration of Treatment (or Duration of Study, if applicable):
Subjects with Normal Renal Function or Severely Impaired Renal Function and Subjects with End-stage Renal
Disease on Continuous Ambulatory Peritoneal Dialysis or Automated Peritoneal Dialysis
After a screening period of up to 30 days prior to study drug administration, eligible subjects were residential
for at least 5 days/4 nights. Subjects were admitted to the clinical unit on day -2 and received a single oral dose
of 100 mg roxadustat in the morning of day 1. The study was completed with an ESV, which took place
between 5 and 9 days after the last treatment period-defined assessment (or after early withdrawal).
Subjects with End-stage Renal Disease on Hemodialysis or Hemodiafiltration
After a screening period of up to 30 days prior to study drug administration, eligible subjects were residential
for at least 5 days/4 nights in each of the 2 treatment periods. The washout between treatment periods 1 and 2
was minimally 1 week and maximally 3 weeks, between day 6 of treatment period 1 and day -1 of treatment
period 2.
In each treatment period, subjects were admitted to the clinical unit on day -2 and received a single oral dose of
100 mg roxadustat in the morning of day 1. The study was completed with an ESV, which took place between 5
and 9 days after the last treatment period 2-defined assessment (or after early withdrawal).
Reference Product, Dose and Mode of Administration, Batch Numbers:
Not applicable
Criteria for Evaluation:
Pharmacokinetics
The pharmacokinetic parameters assessed included the following:
● Pharmacokinetics of roxadustat in plasma: Cmax, Cmax,u, AUCinf, AUCinf,u, AUClast, AUClast,u, CL/F, CLu/F,
fu, tmax, t½, Vz/F and Vz,u/F
● Pharmacokinetics of roxadustat metabolites (O-glucuronide-, O-glucoside- and sulphate of
hydroxy-roxadustat) in plasma: Cmax, AUCinf, AUClast, tlag, tmax, t½ and metabolite to parent ratio (MPR)
● Pharmacokinetics of roxadustat in urine (where possible): CLR, CLR,u, Aeinf, Aeinf%, Aelast and Aelast%
● Pharmacokinetics of roxadustat metabolites (O-glucuronide-, O-glucoside-, and sulphate of
hydroxy-roxadustat) in urine (where possible): CLR, Aeinf, Aelast and MPR based on Aeinf
Roxadustat (FG-4592/ASP1517) ISN 1517-CL-0543Renal AnemiaCONFIDENTIAL EudraCT number 2015-002565-28
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The following additional pharmacokinetic parameters were also calculated, as these were deemed necessary:
● Effective t½ for roxadustat in plasma
● Total exposure ratio (TER) for roxadustat and its metabolites (O-glucuronide-, O-glucoside-, and sulphate
of hydroxy-roxadustat) in plasma
● Aeinf% for roxadustat metabolites in urine (O-glucuronide-, O-glucoside- and sulphate of
hydroxy-roxadustat)
Additional Endpoint for End-stage Renal Disease Subjects on Continuous Ambulatory Peritoneal Dialysis or
Automated Peritoneal Dialysis and for End-stage Renal Disease Subjects on Hemodialysis or Hemodiafiltration
(Treatment Period 2 Only)
The pharmacokinetic parameters in dialysate fluid included the following:
Dialysis clearance (CLD) for roxadustat and its main metabolites
Fraction of dose cleared by dialysis (fD) for roxadustat
All of the pharmacokinetic parameters assessed were considered primary endpoints.
Pharmacodynamics
The pharmacodynamic parameters assessed included the following:
● Pharmacodynamics (EPO): Emax, Emax-baseline, AUCE,last, AUCE,last(baseline-corrected) and tmax,EPO
All of the pharmacodynamic parameters assessed were considered secondary endpoints.
Safety
The safety parameters assessed included the following:
● Nature, frequency and severity of adverse events (AEs)
● Vital signs
● Clinical laboratory tests: hematology, biochemistry and urinalysis
● Routine 12-lead electrocardiogram (ECG)
● Continuous heart rate measurement
All of the safety parameters assessed were considered secondary endpoints.
Statistical Methods:
Pharmacokinetics
Concentrations (plasma, urine and dialysate) and pharmacokinetic parameters of roxadustat and its metabolites
(O-glucuronide-roxadustat, O-glucoside-roxadustat and the sulphate of hydroxy-roxadustat) were summarized
using descriptive statistics by renal function group and treatment period (when applicable). Plasma
concentrations and pharmacokinetic parameters for roxadustat and its metabolites were plotted (as applicable).
An evaluation of the effect of renal function on the pharmacokinetics of roxadustat and its main metabolites was
undertaken by consideration of descriptive statistics and plots of pharmacokinetic parameters.
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Statistical assessments included:
● The effect of dialysis on the pharmacokinetics of roxadustat and its metabolites
● The relationship between total and unbound pharmacokinetic parameters of roxadustat and its metabolites
and eGFR
● Effect of renal function group on pharmacokinetics of roxadustat and its metabolites
Pharmacodynamics
EPO plasma concentrations and pharmacodynamic parameters were summarized using descriptive by renal
function group, treatment period and time point (for concentrations). EPO plasma concentrations were plotted.
Safety
AEs were coded using MedDRA version 19.0. The number and percentage of subjects with treatment-emergent
AEs (TEAEs) were summarized by SOC and preferred term. Descriptive statistics were used to summarize vital
signs, clinical laboratory tests and continuous cardiac monitoring and changes from baseline. Vital signs and
continuous cardiac monitoring were plotted graphically and time-matched changes from baseline.
Summary of Results/Conclusions:
Populations:
Subject classification and analysis sets can be found in Table 1 and demographic and baseline characteristics
can be found in [Table 2].
Pharmacokinetic Results:
● Relative to subjects with normal renal function, the geometric least squares mean ratio for AUCinf of
roxadustat was 223% and 195% in subjects with severely impaired renal function or with ESRD on HD or
HDF, respectively.
● Roxadustat mean Cmax and terminal t½ were comparable between subjects with severely impaired renal
function or with ESRD on HD or HDF and subjects with normal renal function. Mean tmax was delayed in
subjects with severely impaired renal function but not in subjects with ESRD on HD or HDF [Table 3].
● The mean fu of roxadustat in plasma was 1.06% in subjects with severely impaired renal function and
1.10% to 1.16% in subjects with ESRD on HD or HDF, compared with 0.871% in subjects with normal
renal function [Table 3].
● The mean effective t½ for accumulation of roxadustat was 9.71 hours in subjects with normal renal function,
14.9 hours in subjects severely impaired renal function and 15.1 to 15.9 hours in subjects with ESRD on
HD or HDF, calculated for a dosing interval τ of 48 hours [Table 3].
● No metabolite was present in the plasma of subjects with normal renal function, severely impaired renal
function or ESRD on HD or HDF at a mean AUCinf greater than 10% of total drug-related material
[Table 3], [Table 5], [Table 7] and [Table 9].
● Linear regression analysis indicated that CL/F of roxadustat and CLR of roxadustat and metabolites
generally decreased with decreasing eGFR.
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● Roxadustat and metabolites were not significantly cleared by HD or HDF in a 4-hour dialysis session
[Table 4], [Table 6], [Table 8], [Table 10], [Table 15], [Table 16], [Table 17] and [Table 18].
● The percentage of the dose recovered in urine of subjects with normal renal function was 0.978% as
roxadustat, 20.3% as O-glucuronide-roxadustat, 7.21% as O-glucoside-roxadustat and 2.00% as the
sulphate of hydroxy-roxadustat. The urinary excretion of roxadustat and metabolites decreased with
deteriorating renal function [Table 11], [Table 12], [Table 13] and [Table 14].
● One subject with ESRD on CAPD or APD was enrolled in this study and was not used for comparison.
Pharmacodynamic Results:
In subjects with severely impaired renal function or ESRD on HD or HDF, baseline-corrected maximum EPO
values were higher with respect to AUC and Emax than in subjects with normal renal function. Median tmax of
EPO concentrations between 8 and 12 hours did not differ between renal function groups. EPO levels returned
to near baseline at 24 hours postdose in subjects with normal renal function but remained above baseline in
subjects with renal impairment until 36 to 48 hours postdose. Administration of roxadustat in treatment
period 2 (administration before dialysis) resulted in a higher mean AUC and Emax of EPO than administration in
treatment period 1 (administration after dialysis) [Table 19].
Safety Results:
There were no deaths or TEAEs that led to the withdrawal of treatment reported during the conduct of the study.
The highest number and percentage of TEAEs were reported for subjects with normal renal function (12 TEAEs
were reported for 8 [66.7%] subjects). The most commonly reported TEAEs were diarrhea and headache
Table 20 . All TEAEs reported were mild in severity, except for moderate TEAEs of diarrhea, anemia, urinary
tract infection and asthenia. TEAEs considered by the investigator to have a possible or probable relationship to
the study drug comprised tachycardia, diarrhea, nausea, urinary tract infection, headache and maculo-papular
rash.
A serious AE (SAE) of anemia, an SAE (not treatment-emergent) of hyperkalemia and a TEAE of blood
creatine phosphokinase increased were reported during the study. There were no other clinical laboratory
abnormalities that were considered potentially clinically significant by the investigator for any of the clinical
laboratory analyses. Two subjects had alkaline phosphatase values > 1.5 X upper limit of normal; however,
there were no laboratory values that met the criteria for hepatotoxicity or concomitant elevations in alanine
aminotransferase or aspartate aminotransferase with total bilirubin.
Changes reflecting normal diurnal variation were observed for mean systolic blood pressure, diastolic blood
pressure and pulse. One subject with normal renal function had a TEAE of tachycardia. No other individual
vital sign findings were considered by the investigator to be clinically significant.
ECG abnormalities were observed across renal function groups and time points; however, none of these
abnormalities were considered to be clinically significant. For continuous cardiac monitoring, there were no
clinically relevant changes in mean heart rate at time-matched time points on day 1 compared with baseline
(day -1).
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CONCLUSIONS:
Overall, the pharmacokinetics of roxadustat and its main metabolites in subjects with different degrees of renal
function were well characterized. In subjects with severely impaired renal function or with ESRD on HD or
HDF, mean roxadustat plasma exposure (AUC) was approximately double compared with subjects with normal
renal function, whereas Cmax was not significantly changed. The mean TER of roxadustat metabolites was
similar in subjects with severely impaired renal function, with ESRD on HD or HDF and normal renal function
and was not greater than 10% of total drug-related material exposure for any of the circulating metabolites.
Roxadustat and metabolites were not significantly cleared by HD or HDF in a 4-hour dialysis session. A single
dose of 100 mg roxadustat was safe and well tolerated in subjects with different degrees of renal function.
Date of Report: 01 Aug 2018
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Table 1 Subject Classification and Analysis Sets by Renal Function Group (All Registered Subjects)
Analysis Sets
Normal(n = 12)n (%)
Severe(n = 9)n (%)
ESRD on CAPD or APD
(n = 1)n (%)
ESRD on HD or HDF
(n = 12)n (%)
Total
(n = 34)n (%)
Registered 12 (100) 9 (100) 1 (100) 12 (100) 34 (100)
Safety Analysis Set† 12 (100) 9 (100) 1 (100) 12 (100) 34 (100)
Pharmacokinetic Analysis Set‡ 12 (100) 9 (100) 1 (100) 12 (100) 34 (100)
Pharmacodynamic Analysis Set§ 12 (100) 9 (100) 1 (100) 12 (100) 34 (100)
Treatment Discontinuation 0 0 0 0 0
Investigational Period Discontinuation
0 0 0 0 0
Follow-up Discontinuation 0 0 0 0 0
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration.
† All enrolled subjects who received at least 1 dose of study drug (roxadustat).
‡ A subset of the safety analysis set for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
§ A subset of the safety analysis set population for which sufficient pharmacodynamics data was available to facilitate derivation of at least 1 pharmacodynamic parameter and for whom the time of dosing on the day of sampling was known.
Source: End-of-Text Tables 12.1.1.1, 12.1.1.3.1, 12.1.1.4 and 12.1.1.5
Table 2 Summary of Demographic and Baseline Characteristics by Renal Function Group (All Registered Subjects)
ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 9)
ESRD on CAPD or APD
(n = 1)
ESRD on HD or HDF
(n = 12)
Total
(n = 34)
Sex, n (%)
Male 5 (41.7) 6 (66.7) 1 (100) 9 (75.0) 21 (61.8)
Female 7 (58.3) 3 (33.3) 0 3 (25.0) 13 (38.2)
Race, n (%)
White 12 (100) 9 (100) 1 (100) 12 (100) 34 (100.0)
Black or African American 0 0 0 0 0
Asian 0 0 0 0 0
American Indian or Alaska Native
0 0 0 0 0
Native Hawaiian or Other Pacific Islander
0 0 0 0 0
Other 0 0 0 0 0
Age (years)
Mean (SD) 60.1 (11.4) 64.3 (6.6) 56.0 (NA) 56.3 (10.8) 59.8 (10.1)
Median 62.0 65.0 56.0 53.0 61.0
Min - Max 45 - 75 55 - 73 56 - 56 37 - 75 37 - 75
EudraCT Age Category, n (%)
≥ 18 years to ≤ 64 years 8 (66.7) 4 (44.4) 1 (100) 10 (83.3) 23 (67.6)
≥ 65 years to ≤ 84 years 4 (33.3) 5 (55.6) 0 2 (16.7) 11 (32.4)
≥ 85 years 0 0 0 0 0
Table continued on next page
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ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 9)
ESRD on CAPD or APD
(n = 1)
ESRD on HD or HDF
(n = 12)
Total
(n = 34)
Weight (kg)
Mean (SD) 77.73 (12.40) 90.46 (21.08) 72.60 (NA) 76.78 (14.58) 80.61 (16.33)
Median 78.50 98.00 72.60 76.55 80.20
Min - Max 57.2 - 98.4 52.1 - 114.2 72.6 - 72.6 50.7 - 107.2 50.7 - 114.2
Height (cm)
Mean (SD) 169.2 (9.1) 173.6 (9.3) 182.0 (NA) 169.2 (7.7) 170.7 (8.7)
Median 166.0 173.0 182.0 170.0 170.5
Min - Max 158 - 183 158 - 186 182 - 182 155 - 181 155 - 186
BMI (kg/m2)
Mean (SD) 27.38 (5.52) 30.35 (8.37) 21.92 (NA) 26.72 (4.10) 27.77 (6.01)
Median 26.67 28.83 21.92 26.27 26.82
Min - Max 21.0 - 39.4 16.4 - 45.8 21.9 - 21.9 21.1 - 33.8 16.4 – 45.8
eGFR (mL/min/1.73 m2)
Mean (SD)105.74 (12.32)
16.91 (6.45) 8.76 (NA) 8.59 (2.87) 45.09 (46.28)
Median 102.49 14.22 8.76 8.10 14.14
Min - Max 92.4 - 128.9 9.7 - 27.1 8.8 - 8.8 3.8 - 13.4 3.8 – 128.9
All eligible (i.e., not screen failures) subjects.
APD: automated peritoneal dialysis; BMI: body mass index (weight [kg]/height2 [m2]); CAPD: continuous ambulatory peritoneal dialysis; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; max: maximum; min: minimum; NA: not applicable.
Source: End-of-Text Table 12.1.2.1
Table 3 Plasma Pharmacokinetic Parameters of Roxadustat by Renal Function Group(Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 9)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12)
ESRD on HD or HDF
Treatment Period 2(n = 12)
Cmax (ng/mL)
Mean (SD) 6780 (1460) 6730 (1310) 6010 (NA) 6950 (1850) 6910 (1290)
%CV 21.6 19.5 NA 26.6 18.6
Median 6780 6750 6010 7140 7440
Min - Max 4740 – 9400 4540 – 9250 6010 – 6010 3090 – 9700 4890 – 8540
AUCinf (h•ng/mL)
Mean (SD) 39800 (8780) 82500 (18300) 74900 (NA) 77400 (29500) 76600 (28200)
%CV 22.1 22.2 NA 38.1 36.9
Median 38300 78500 74900 73000 73200
Min - Max 28400 – 59200 61300 – 116000 74900 – 74900 43900 – 134000 43100 – 130000
AUClast (h•ng/mL)
Mean (SD) 39600 (8600) 81900 (18200) 74800 (NA) 76300 (28100) 75500 (26800)
%CV 21.7 22.2 NA 36.8 35.4
Median 38200 77900 74800 71300 72700
Min - Max 28400 – 58400 61200 – 116000 74800 – 74800 43800 – 131000 43000 – 125000
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ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 9)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12)
ESRD on HD or HDF
Treatment Period 2(n = 12)
CL/F (L/h)
Mean (SD) 2.62 (0.536) 1.26 (0.268) 1.34 (NA) 1.45 (0.472) 1.47 (0.510)
%CV 20.4 21.2 NA 32.6 34.7
Median 2.62 1.27 1.34 1.37 1.37
Min - Max 1.69 – 3.52 0.859 – 1.63 1.34 – 1.34 0.745 – 2.28 0.769 – 2.32
tmax (h)
Median 1.00 3.00 3.00 2.00 1.00
Min - Max 0.983 – 3.00 1.00 – 4.00 3.00 – 3.00 0.967 – 5.00 0.967 – 4.00
t½ (h)
Mean (SD) 16.0 (6.75) 18.5 (4.41) 12.5 (NA) 17.2 (6.97) 16.8 (5.55)
%CV 42.3 23.8 NA 40.4 33.0
Median 13.8 17.2 12.5 15.3 15.0
Min - Max 8.31 – 33.0 13.1 – 24.8 12.5 – 12.5 11.3 – 33.0 9.57 – 28.2
Vz/F (L)
Mean (SD) 57.2 (15.2) 33.8 (10.5) 24.1 (NA) 33.8 (11.4) 33.1 (8.22)
%CV 26.6 31.1 NA 33.8 24.9
Median 52.9 35.7 24.1 35.7 33.1
Min - Max 32.6 – 80.5 20.9 – 49.9 24.1 – 24.1 18.6 – 54.9 18.1 – 47.2
Effective t½ 48 hours (h)
Mean (SD) 9.71 (1.35) 14.9 (2.97) 13.3 (NA) 15.9 (4.56) 15.1 (4.14)
%CV 13.9 19.9 NA 28.7 27.4
Median 9.88 13.7 13.3 14.6 14.3
Min - Max 7.47 – 12.2 10.3 – 19.5 13.3 – 13.3 11.1 – 22.7 11.3 – 25.5
Effective t½ 56 hours (h)
Mean (SD) 10.3 (1.60) 15.3 (2.98) 13.2 (NA) 16.1 (4.52) 15.5 (4.25)
%CV 15.6 19.5 NA 28.1 27.4
Median 10.1 14.1 13.2 15.0 14.7
Min - Max 7.53 – 13.3 10.7 – 19.8 13.2 – 13.2 11.4 – 22.6 11.5 – 25.7
fu
Mean (SD) 0.00871 (0.000653) 0.0106 (0.00121) 0.00880 (NA) 0.0110 (0.000859) 0.0116 (0.00114)
%CV 7.5 11.4 NA 7.8 9.8
Median 0.00877 0.0106 0.00880 0.0115 0.0113
Min - Max 0.00765 – 0.00985 0.00834 – 0.0127 0.00880 – 0.00880 0.00962 – 0.0118 0.00998 – 0.0135
Cmax,u (ng/mL)
Mean (SD) 59.1 (13.4) 70.6 (10.3) 52.9 (NA) 76.3 (21.1) 80.0 (16.4)
%CV 22.6 14.6 NA 27.7 20.4
Median 59.2 72.7 52.9 72.8 84.5
Min - Max 36.3 – 82.1 47.2 – 83.2 52.9 – 52.9 36.6 – 109 51.0 – 102
AUCinf,u (h•ng/mL)
Mean (SD) 348 (85.1) 872 (203) 659 (NA) 850 (333) 898 (372)
%CV 24.5 23.3 NA 39.2 41.4
Median 345 857 659 746 859
Min - Max 237 – 520 653 – 1190 659 – 659 513 – 1570 430 – 1600
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ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 9)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12)
ESRD on HD or HDF
Treatment Period 2(n = 12)
AUClast,u (h•ng/mL)
Mean (SD) 346 (83.7) 864 (198) 658 (NA) 838 (319) 886 (353)
%CV 24.2 22.9 NA 38.1 39.9
Median 344 849 658 728 855
Min - Max 236 – 513 651 – 1180 658 – 658 512 – 1530 429 – 1520
CLu/F (L/h)
Mean (SD) 303 (71.8) 120 (25.6) 152 (NA) 132 (41.3) 130 (54.6)
%CV 23.7 21.3 NA 31.3 41.9
Median 290 117 152 134 116
Min - Max 192 – 423 84.2 – 153 152 – 152 63.7 – 195 62.4 – 233
Vz,u/F (L)
Mean (SD) 6620 (1890) 3160 (855) 2740 (NA) 3110 (1130) 2900 (856)
%CV 28.6 27.1 NA 36.5 29.6
Median 6180 3150 2740 3220 2740
Min - Max 3630 – 9150 2090 – 4800 2740 – 2740 1600 – 5400 1600 – 4740
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; NA: not applicable.
Source: End-of-Text Table 12.4.2.1.1
Table 4 Statistical Assessment of the Effect of Dialysis on Plasma Pharmacokinetics of Roxadustat in Subjects With End-stage Renal Disease on Hemodialysis or Hemodiafiltration (Pharmacokinetic Analysis Set)
Parameter
Treatment Period 1 Treatment Period 2 Geometric LS Mean Ratio
(%)90% CI of Ratio (%)n
Geometric LS Mean n
Geometric LS Mean
AUCinf (h∙ng/mL) 12 72900 12 72200 98.95 (92.40, 105.96)
Cmax (ng/mL) 12 6690 12 6790 101.62 (90.78, 113.76)
AUCinf,u (h∙ng/mL) 12 799 12 831 103.92 (95.43, 113.16)
Cmax.u (ng/mL) 12 73.3 12 78.2 106.72 (92.60, 123.01)
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
Assessment based on an analysis of variance performed on natural logarithmic-transformed parameters with treatment period as a fixed effect and subject as a random effect.
Ratios and CIs are transformed back to raw scale and values are expressed as percentages.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; LS: least squares.
Source: End-of-Text Table 12.4.3.1.1
Roxadustat (FG-4592/ASP1517) ISN 1517-CL-0543Renal AnemiaCONFIDENTIAL EudraCT number 2015-002565-28
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Table 5 Plasma Pharmacokinetic Parameters of O-glucuronide-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12†)
Severe(n = 9)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12)
ESRD on HD or HDF
Treatment Period 2(n = 12‡)
Cmax (ng/mL)
Mean (SD) 49.9 (16.0) 38.1 (19.9) 18.3 (NA) 59.2 (50.9) 55.1 (43.9)
%CV 32.0 52.4 NA 85.9 79.8
Median 46.9 30.8 18.3 37.2 36.5
Min - Max 30.4 – 86.9 23.6 – 89.1 18.3 – 18.3 17.1 – 167 21.2 – 157
AUCinf (h•ng/mL)
Mean (SD) 286 (88.2) 533 (320) 253 (NA) 1080 (1490) 924 (1240)
%CV 30.8 60.1 NA 137.5 133.9
Median 263 446 253 449 382
Min - Max 186 – 491 240 – 1320 253 – 253 181 – 5040 156 – 4420
AUClast (h•ng/mL)
Mean (SD) 277 (87.7) 516 (320) 235 (NA) 1040 (1460) 887 (1190)
%CV 31.6 62.0 NA 140.0 134.0
Median 257 428 235 427 353
Min - Max 174 – 481 228 – 1300 235 – 235 157 – 4980 146 – 4220
tlag (h)
Median 0 0.500 1.00 0 0
Min - Max 0 – 0.500 0 – 1.05 1.00 – 1.00 0 – 1.00 0 – 1.00
tmax (h)
Median 2.00 3.00 4.00 2.00 2.01
Min - Max 1.00 – 3.00 3.00 – 5.00 4.00 – 4.00 1.00 – 8.00 1.95 – 5.00
t½ (h)
Mean (SD) 8.10 (1.86) 15.9 (5.35) 11.1 (NA) 17.5 (9.19) 17.2 (5.97)
%CV 23.0 33.6 NA 52.6 34.7
Median 8.36 14.6 11.1 14.1 16.0
Min - Max 4.54 – 10.5 9.46 – 23.6 11.1 – 11.1 10.0 – 39.8 9.93 – 27.7
MPR
Mean (SD) 0.00495 (0.00159) 0.00432 (0.00224) 0.00225 (NA) 0.00779 (0.00743) 0.00666 (0.00607)
%CV 32.2 51.9 NA 95.3 91.1
Median 0.00463 0.00369 0.00225 0.00451 0.00371
Min - Max 0.00252 – 0.00803 0.00229 – 0.00941 0.00225 – 0.00225 0.00206 – 0.0250 0.00242 – 0.0227
TER
Mean (SD) 0.00478 (0.00156) 0.00402 (0.00203) 0.00214 (NA) 0.00704 (0.00652) 0.00641 (0.00547)
%CV 32.6 50.5 NA 92.6 85.4
Median 0.00457 0.00339 0.00214 0.00414 0.00357
Min - Max 0.00240 – 0.00765 0.00210 – 0.00860 0.00214 – 0.00214 0.00197 – 0.0218 0.00229 – 0.0199
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
MPR and TER were calculated according to Astellas NCA manual version 2.0; MPR = AUCcorr(M)/AUC(P)and TER = AUClast(corr)(M)/(AUC[P] + sum of AUClast(corr) [M] for all 3 metabolites quantified).
Footnotes continued on next page
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APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable; NCA: noncompartmental analysis; TER: total exposure ratio.
† n = 10 for TER
‡ n = 11 for TER
Source: End-of-Text Table 12.4.2.1.2
Table 6 Statistical Assessment of the Effect of Dialysis on Plasma Pharmacokinetics of O-glucuronide-roxadustat in Subjects With End-stage Renal Disease on Hemodialysis or Hemodiafiltration (Pharmacokinetic Analysis Set)
Parameter
Treatment Period 1 Treatment Period 2 Geometric LS Mean Ratio
(%)90% CI of Ratio (%)n
Geometric LS Mean n
Geometric LS Mean
AUCinf (h∙ng/mL) 12 610 12 545 89.41 (80.92, 98.78)
Cmax (ng/mL) 12 44.9 12 43.9 97.73 (87.83, 108.74)
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
Assessment based on an analysis of variance performed on natural logarithmic-transformed parameters with treatment period as a fixed effect and subject as a random effect.
Ratios and CIs are transformed back to raw scale and values are expressed as percentages.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; LS: least squares.
Source: End-of-Text Table 12.4.3.1.2
Table 7 Plasma Pharmacokinetic Parameters of O-glucoside-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12†)
Severe(n = 9)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12)
ESRD on HD or HDF
Treatment Period 2(n = 12‡)
Cmax (ng/mL)
Mean (SD) 18.3 (9.85) 27.6 (9.98) 10.8 (NA) 21.7 (12.4) 21.9 (11.7)
%CV 53.7 36.1 NA 57.4 53.6
Median 15.9 24.3 10.8 18.5 18.7
Min - Max 8.80 – 39.7 15.8 – 45.7 10.8 – 10.8 8.01 – 52.0 5.41 – 49.9
AUCinf (h•ng/mL)
Mean (SD) 146 (87.8) 495 (296) 164 (NA) 369 (346) 375 (391)
%CV 60.3 59.7 NA 93.7 104.4
Median 109 470 164 241 231
Min - Max 74.4 – 347 158 – 1080 164 – 164 115 – 1320 72.2 – 1410
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ParameterCategory/Statistics
Normal(n = 12†)
Severe(n = 9)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12)
ESRD on HD or HDF
Treatment Period 2(n = 12‡)
AUClast (h•ng/mL)
Mean (SD) 121 (84.2) 477 (294) 149 (NA) 347 (338) 342 (370)
%CV 69.6 61.6 NA 97.3 108.1
Median 94.6 440 149 224 203
Min - Max 44.2 – 328 150 – 1050 149 – 149 93.7 – 1280 65.7 – 1380
tlag (h)
Median 0.475 0.500 1.00 0.492 0
Min - Max 0 – 1.00 0 – 1.05 1.00 – 1.00 0 – 2.00 0 – 2.03
tmax (h)
Median 2.99 3.00 4.00 3.00 3.00
Min - Max 1.97 – 3.00 3.00 – 4.00 4.00 – 4.00 2.00 – 8.00 1.95 – 12.0
t½ (h)
Mean (SD) 8.48 (2.97) 15.2 (3.56) 12.7 (NA) 14.6 (5.99) 15.4 (4.36)
%CV 35.0 23.4 NA 41.1 28.3
Median 7.84 15.6 12.7 13.2 15.1
Min - Max 5.89 – 15.4 10.3 – 19.7 12.7 – 12.7 8.35 – 28.8 6.71 – 21.8
MPR
Mean (SD) 0.00246 (0.00126) 0.00406 (0.00195) 0.00150 (NA) 0.00297 (0.00159) 0.00296 (0.00193)
%CV 51.3 48.0 NA 53.5 65.3
Median 0.00218 0.00427 0.00150 0.00237 0.00242
Min - Max 0.000861 – 0.00526 0.00120 – 0.00643 0.00150 – 0.00150 0.00135 – 0.00673 0.00115 – 0.00743
TER
Mean (SD) 0.00228 (0.00114) 0.00378 (0.00179) 0.00143 (NA) 0.00270 (0.00137) 0.00269 (0.00169)
%CV 50.0 47.4 NA 50.7 62.8
Median 0.00208 0.00405 0.00143 0.00219 0.00218
Min - Max 0.000822 – 0.00480 0.00117 – 0.00594 0.00143 – 0.00143 0.00129 – 0.00586 0.00109 – 0.00653
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
MPR and TER were calculated according to Astellas NCA manual version 2.0; MPR = AUCcorr(M)/AUC(P)and TER = AUClast(corr),(M)/(AUC[P] + sum of AUClast(corr) [M] for all 3 metabolites quantified).
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable; NCA: noncompartmental analysis; TER: total exposure ratio.
† n = 10 for AUCinf, t½, MPR and TER
‡ n = 11 for AUCinf, t½, MPR and TER
Source: End-of-Text Table 12.4.2.1.3
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Table 8 Statistical Assessment of the Effect of Dialysis on Plasma Pharmacokinetics of O-glucoside-roxadustat in Subjects With End-stage Renal Disease on Hemodialysis or Hemodiafiltration (Pharmacokinetic Analysis Set)
Parameter
Treatment Period 1 Treatment Period 2 Geometric LS Mean Ratio
(%)90% CI of Ratio (%)n
Geometric LS Mean n
Geometric LS Mean
AUCinf (h∙ng/mL) 12 281 11 253 89.91 (79.93, 101.13)
Cmax (ng/mL) 12 18.8 12 19.1 101.33 (91.61, 112.07)
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
Assessment based on an analysis of variance performed on natural logarithmic-transformed parameters with treatment period as a fixed effect and subject as a random effect.
Ratios and CIs are transformed back to raw scale and values are expressed as percentages.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; LS: least squares.
Source: End-of-Text Table 12.4.3.1.3
Table 9 Plasma Pharmacokinetic Parameters of Sulphate of Hydroxy-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12†)
Severe(n = 9)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12)
ESRD on HD or HDF
Treatment Period 2(n = 12‡)
Cmax (ng/mL)
Mean (SD) 635 (230) 453 (225) 435 (NA) 623 (222) 627 (193)
%CV 36.2 49.7 NA 35.6 30.8
Median 561 460 435 622 614
Min - Max 303 – 1140 226 – 866 435 – 435 285 – 903 232 – 915
AUCinf (h•ng/mL)
Mean (SD) 3590 (1150) 6390 (2840) 4590 (NA) 8310 (5910) 7720 (4690)
%CV 32.1 44.4 NA 71.1 60.8
Median 3250 6170 4590 7190 6460
Min - Max 1690 – 5620 2560 – 10500 4590 – 4590 2820 – 20700 2940 – 17700
AUClast (h•ng/mL)
Mean (SD) 3540 (1160) 6330 (2810) 4530 (NA) 8140 (5700) 7560 (4510)
%CV 32.6 44.4 NA 70.0 59.6
Median 3220 6110 4530 7160 6400
Min - Max 1670 – 5590 2530 – 10500 4530 – 4530 2780 – 19700 2900 – 17100
tlag (h)
Median 0 0.500 1.00 0 0
Min - Max 0 – 0.500 0 – 1.05 1.00 – 1.00 0 – 1.00 0 – 1.00
tmax (h)
Median 2.02 5.00 4.00 2.00 2.00
Min - Max 1.97 – 4.00 3.00 – 6.00 4.00 – 4.00 1.97 – 12.0 1.95 – 5.98
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ParameterCategory/Statistics
Normal(n = 12†)
Severe(n = 9)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12)
ESRD on HD or HDF
Treatment Period 2(n = 12‡)
t½ (h)
Mean (SD) 15.9 (6.12) 18.6 (6.72) 12.8 (NA) 18.2 (6.59) 18.7 (5.74)
%CV 38.4 36.1 NA 36.2 30.7
Median 14.1 17.4 12.8 17.5 16.9
Min - Max 9.00 – 26.3 11.7 – 35.0 12.8 – 12.8 12.0 – 31.8 11.7 – 30.2
MPR
Mean (SD) 0.0725 (0.0227) 0.0606 (0.0227) 0.0482 (NA) 0.0779 (0.0256) 0.0747 (0.0208)
%CV 31.3 37.4 NA 32.8 27.8
Median 0.0743 0.0710 0.0482 0.0725 0.0745
Min - Max 0.0391 – 0.106 0.0253 – 0.0849 0.0482 – 0.0482 0.0449 – 0.123 0.0472 – 0.107
TER
Mean (SD) 0.0643 (0.0194) 0.0563 (0.0202) 0.0458 (NA) 0.0710 (0.0212) 0.0702 (0.0173)
%CV 30.2 35.9 NA 29.8 24.7
Median 0.0687 0.0656 0.0458 0.0672 0.0697
Min - Max 0.0373 – 0.0893 0.0246 – 0.0779 0.0458 – 0.0458 0.0428 – 0.107 0.0444 – 0.0942
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
MPR and TER were calculated according to Astellas NCA manual version 2.0; MPR = AUCcorr(M)/AUC(P)and TER = AUClast(corr)(M)/(AUC[P] + sum of AUClast(corr) [M] for all 3 metabolites quantified).
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable; NCA: noncompartmental analysis; TER: total exposure ratio.
† n = 10 for TER
‡ n = 11 for TER
Source: End-of-Text Table 12.4.2.1.4
Table 10 Statistical Assessment of the Effect of Dialysis on Plasma Pharmacokinetics of Sulphate of Hydroxy-roxadustat in Subjects With End-stage Renal Disease on Hemodialysis or Hemodiafiltration (Pharmacokinetic Analysis Set)
Parameter
Treatment Period 1 Treatment Period 2 Geometric LS Mean Ratio
(%)90% CI of Ratio (%)n
Geometric LS Mean n
Geometric LS Mean
AUCinf (h∙ng/mL) 12 6890 12 6610 96.05 (89.53, 103.04)
Cmax (ng/mL) 12 580 12 594 102.32 (90.39, 115.82)
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
Assessment based on an analysis of variance performed on natural logarithmic-transformed parameters with treatment period as a fixed effect and subject as a random effect.
Ratios and CIs are transformed back to raw scale and values are expressed as percentages.
Footnotes continued on next page
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For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; LS: least squares.
Source: End-of-Text Table 12.4.3.1.4
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Table 11 Urine Pharmacokinetic Parameters of Roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 9†)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDFTreatment Period 1
(n = 12‡)
ESRD on HD or HDFTreatment Period 2
(n = 12‡)
CLR (L/h)
Mean (SD) 0.0260 (0.0159) 0.00949 (0.00648) 0.00613 (NA) 0.00138 (0.00131) 0.00118 (0.00112)
%CV 61.4 68.3 NA 94.7 94.7
Median 0.0231 0.00775 0.00613 0.00139 0.000891
Min - Max 0.00492 – 0.0585 0.00271 – 0.0252 0.00613 – 0.00613 0.0000195 – 0.00398 0.0000344 – 0.00355
Aeinf (mg)
Mean (SD) 0.978 (0.531) 0.773 (0.588) 0.459 (NA) 0.1000 (0.101) 0.104 (0.145)
%CV 54.3 76.0 NA 100.4 139.3
Median 0.948 0.734 0.459 0.0897 0.0613
Min - Max 0.202 – 2.04 0.264 – 2.27 0.459 – 0.459 0.00111 – 0.303 0.00233 – 0.450
Aeinf%
Mean (SD) 0.978 (0.531) 0.773 (0.588) 0.459 (NA) 0.1000 (0.101) 0.104 (0.145)
%CV 54.3 76.0 NA 100.4 139.3
Median 0.948 0.734 0.459 0.0897 0.0613
Min - Max 0.202 – 2.04 0.264 – 2.27 0.459 – 0.459 0.00111 – 0.303 0.00233 – 0.450
Aelast (mg)
Mean (SD) 0.965 (0.525) 0.791 (0.607) 0.450 (NA) 0.0927 (0.0895) 0.0979 (0.133)
%CV 54.4 76.7 NA 96.5 135.7
Median 0.935 0.679 0.450 0.0836 0.0589
Min - Max 0.200 – 2.03 0.257 – 2.24 0.450 – 0.450 0.00107 – 0.264 0.00226 – 0.414
Aelast%
Mean (SD) 0.965 (0.525) 0.791 (0.607) 0.450 (NA) 0.0927 (0.0895) 0.0979 (0.133)
%CV 54.4 76.7 NA 96.5 135.7
Median 0.935 0.679 0.450 0.0836 0.0589
Min - Max 0.200 – 2.03 0.257 – 2.24 0.450 – 0.450 0.00107 – 0.264 0.00226 – 0.414
CLR,u (L/h)
Mean (SD) 2.99 (1.81) 0.947 (0.815) 0.697 (NA) 0.126 (0.114) 0.105 (0.0932)
%CV 60.5 86.1 NA 90.2 88.9
Median 2.62 0.692 0.697 0.128 0.0819
Min - Max 0.562 – 6.45 0.280 – 3.02 0.697 – 0.697 0.00172 – 0.340 0.00263 – 0.296
Footnotes appear on next page
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All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable.
† n = 8 for Aelast and Aelast%
‡ n = 8 for CLR, Aeinf, Aeinf%, Aelast, Aelast% and CLR,u
Source: End-of-Text Table 12.4.2.2.1
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Table 12 Urine Pharmacokinetic Parameters of O-glucuronide-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 9†)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12‡)
ESRD on HD or HDF
Treatment Period 2(n = 12‡)
CLR (L/h)Mean (SD) 114 (44.3) 30.5 (21.0) 18.9 (NA) 2.58 (2.96) 2.12 (2.57)%CV 38.7 68.8 NA 114.7 121.2Median 130 20.4 18.9 0.998 0.825Min - Max 44.6 – 167 7.18 – 61.9 18.9 – 18.9 0.00618 – 7.14 0.000461 – 7.45
Aeinf (mg)Mean (SD) 30.5 (8.53) 12.8 (6.69) 4.77 (NA) 1.29 (1.27) 1.02 (1.05)%CV 28.0 52.3 NA 98.6 103.8Median 34.5 9.64 4.77 1.02 0.717Min - Max 11.4 – 37.3 6.82 – 26.7 4.77 – 4.77 0.00221 – 3.70 0.000154 – 3.20
Aeinf%Mean (SD) 20.3 (5.69) 8.52 (4.46) 3.18 (NA) 0.861 (0.849) 0.677 (0.703)%CV 28.0 52.3 NA 98.6 103.8Median 23.0 6.43 3.18 0.678 0.478Min - Max 7.61 – 24.9 4.55 – 17.8 3.18 – 3.18 0.00148 – 2.47 0.000103 – 2.13
Aelast (mg)Mean (SD) 31.2 (8.73) 12.8 (6.42) 4.79 (NA) 1.17 (1.08) 0.954 (0.934)%CV 28.0 50.1 NA 91.9 97.9Median 35.8 10.8 4.79 1.00 0.722Min - Max 11.9 – 37.6 6.49 – 24.4 4.79 – 4.79 0.00166 – 3.17 0.000115 – 2.85
MPR Based on Aeinf
Mean (SD) 26.2 (14.8) 12.9 (5.47) 6.92 (NA) 11.1 (13.4) 9.16 (9.79)%CV 56.4 42.6 NA 120.2 106.8Median 20.3 11.7 6.92 5.10 4.66Min - Max 12.2 – 62.0 6.08 – 24.3 6.92 – 6.92 1.01 – 38.0 0.0440 – 27.9
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable.
† n = 8 for Aelast
‡ n = 8 for CLR, Aeinf, Aeinf%, Aelast and MPR based on Aeinf
Source: End-of-Text Table 12.4.2.2.2
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Table 13 Urine Pharmacokinetic Parameters of O-glucoside-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12†)
Severe(n = 9‡)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 12§)
ESRD on HD or HDF
Treatment Period 2(n = 12¶)
CLR (L/h)
Mean (SD) 99.8 (49.2) 13.3 (13.8) 10.4 (NA) 1.77 (1.61) 1.86 (2.59)
%CV 49.3 104.0 NA 91.0 139.3
Median 101 5.52 10.4 1.23 1.20
Min - Max 33.4 – 181 4.15 – 41.5 10.4 – 10.4 0.00355 – 4.81 0.000505 – 7.49
Aeinf (mg)
Mean (SD) 10.5 (3.28) 4.13 (1.91) 1.71 (NA) 0.410 (0.316) 0.394 (0.511)
%CV 31.2 46.2 NA 77.1 129.4
Median 11.4 3.31 1.71 0.329 0.264
Min - Max 3.87 – 14.6 1.59 – 6.54 1.71 – 1.71 0.000989 – 0.999 0.000158 – 1.41
Aeinf%
Mean (SD) 7.21 (2.25) 2.83 (1.31) 1.17 (NA) 0.281 (0.217) 0.270 (NA)
%CV 31.2 46.2 NA 77.1 NA
Median 7.81 2.27 1.17 0.226 0.181
Min - Max 2.65 – 10.0 1.09 – 4.48 1.17 – 1.17 0.000677 – 0.684 0.000108 – 0.966
Aelast (mg)
Mean (SD) 10.5 (3.15) 4.07 (1.90) 1.68 (NA) 0.404 (0.338) 0.339 (0.479)
%CV 30.1 46.5 NA 83.8 141.3
Median 11.1 4.31 1.68 0.314 0.239
Min - Max 3.88 – 15.1 1.52 – 6.40 1.68 – 1.68 0.000893 – 1.08 0.000148 – 1.39
MPR Based on Aeinf
Mean (SD) 10.2 (6.54) 4.15 (1.36) 2.55 (NA) 3.35 (3.03) 3.98 (4.45)
%CV 64.4 32.7 NA 90.4 111.8
Median 8.88 4.12 2.55 2.05 2.83
Min - Max 3.63 – 25.1 1.97 – 5.74 2.55 – 2.55 0.612 – 8.33 0.0465 – 12.6
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable.
† n = 10 for Aeinf, Aeinf% and MPR based on Aeinf
‡ n = 8 for Aelast
§ n = 7 for CLR, Aeinf, Aeinf%, Aelast and MPR based on Aeinf
¶ n = 7 for CLR and Aelast and n = 6 for Aeinf, Aeinf% and MPR based on Aeinf
Source: End-of-Text Table 12.4.2.2.3
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Table 14 Urine Pharmacokinetic Parameters of Sulphate of Hydroxy-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 9†)
ESRD on CAPD or APD(n = 1)
ESRD on HD or HDFTreatment Period 1
(n = 12‡)
ESRD on HD or HDFTreatment Period 2
(n = 12‡)
CLR (L/h)
Mean (SD) 0.735 (0.210) 0.0852 (0.0452) 0.0354 (NA) 0.0121 (0.00685) 0.00895 (0.00865)
%CV 28.6 53.0 NA 56.6 96.7
Median 0.780 0.0667 0.0354 0.0117 0.00802
Min - Max 0.326 – 0.948 0.0533 – 0.191 0.0354 – 0.0354 0.0000517 – 0.0192 0.00000777 – 0.0237
Aeinf (mg)
Mean (SD) 2.55 (0.949) 0.506 (0.291) 0.163 (NA) 0.0756 (0.0527) 0.0486 (0.0547)
%CV 37.2 57.6 NA 69.7 112.5
Median 2.55 0.430 0.163 0.0662 0.0341
Min - Max 1.28 – 4.16 0.217 – 1.18 0.163 – 0.163 0.000386 – 0.160 0.0000534 – 0.143
Aeinf%
Mean (SD) 2.00 (0.746) 0.397 (0.229) 0.128 (NA) 0.0594 (0.0414) 0.0382 (0.0429)
%CV 37.2 57.6 NA 69.7 112.5
Median 2.00 0.338 0.163 0.0520 0.0268
Min - Max 1.01 – 3.27 0.171 – 0.926 0.128 – 0.128 0.000303 – 0.126 0.0000420 – 0.112
Aelast (mg)
Mean (SD) 2.51 (0.932) 0.509 (0.277) 0.154 (NA) 0.0640 (0.0468) 0.0449 (0.0505)
%CV 37.0 54.5 NA 73.1 112.5
Median 2.51 0.432 0.154 0.0572 0.0335
Min - Max 1.27 – 4.10 0.200 – 1.10 0.154 – 0.154 0.000372 – 0.136 0.0000411 – 0.134
MPR Based on Aeinf
Mean (SD) 2.81 (2.26) 0.724 (0.603) 0.278 (NA) 0.774 (0.750) 0.648 (0.632)
%CV 80.3 83.2 NA 96.9 97.5
Median 1.89 0.559 0.278 0.645 0.582
Min - Max 1.08 – 8.20 0.125 – 2.09 0.278 – 0.278 0.138 – 2.38 0.0180 – 1.52
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
Footnotes continued on next page
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APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable.
† n = 8 for Aelast
‡ n = 7 for CLR, Aeinf, Aeinf%, Aelast and MPR based on Aeinf
Source: End-of-Text Table 12.4.2.2.4
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Table 15 Dialysate Pharmacokinetic Parameters of Roxadustat (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
ESRD on CAPD or APD(n = 1†)
ESRD on HD or HDFTreatment Period 2
(n = 12)
CLD (L/h)
Mean (SD) NA (NA) 0.128 (0.0584)
%CV NA 45.6
Median NA 0.143
Min – Max NA – NA 0.0186 – 0.195
fD
Mean (SD) 0.00371 (NA) 0.0234 (0.0126)
%CV NA 54.0
Median 0.00371 0.0266
Min – Max 0.00371 – 0.00371 0.00229 – 0.0450
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whomthe time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
Dialysate pharmacokinetic parameters account for the incorrect volume unit for 1 subject with ESRD on HD or HDF.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; NA: not applicable.
† n = 0 for CLD
Source: End-of-Text Table 12.4.2.3.1
Table 16 Dialysate Pharmacokinetic Parameters of O-glucuronide-roxadustat (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
ESRD on CAPD or APD(n = 1†)
ESRD on HD or HDFTreatment Period 2
(n = 12)
CLD (L/h)
Mean (SD) NA (NA) 0.00300 (0.00133)
%CV NA 44.2
Median NA 0.00335
Min – Max NA – NA 0.000435 – 0.00474
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
Dialysate pharmacokinetic parameters account for the incorrect volume unit for 1 subject with ESRD on HD or HDF.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; NA: not applicable.
† n = 0 for CLD
Source: End-of-Text Table 12.4.2.3.2
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Table 17 Dialysate Pharmacokinetic Parameters of O-glucoside-roxadustat (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
ESRD on CAPD or APD(n = 1†)
ESRD on HD or HDFTreatment Period 2
(n = 12)
CLD (L/h)
Mean (SD) NA (NA) 0.00363 (0.00161)
%CV NA 44.3
Median NA 0.00391
Min – Max NA – NA 0.000520 – 0.00585
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
Dialysate pharmacokinetic parameters account for the incorrect volume unit for 1 subject with ESRD on HD or HDF.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; NA: not applicable.
† n = 0 for CLD
Source: End-of-Text Table 12.4.2.3.3
Table 18 Dialysate Pharmacokinetic Parameters of Sulphate of Hydroxy-roxadustat (Pharmacokinetic Analysis Set)
ParameterCategory/Statistics
ESRD on CAPD or APD(n = 1†)
ESRD on HD or HDFTreatment Period 2
(n = 12)
CLD (L/h)
Mean (SD) NA (NA) 0.0000528 (0.0000268)
%CV NA 50.6
Median NA 0.0000508
Min – Max NA – NA 0.00000671 – 0.000104
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
Dialysate pharmacokinetic parameters account for the incorrect volume unit for 1 subject with ESRD on HD or HDF.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; NA: not applicable.
† n = 0 for CLD
Source: End-of-Text Table 12.4.2.3.4
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Table 19 Plasma Pharmacodynamic Parameters of Erythropoietin by Renal Function Group(Pharmacodynamic Analysis Set)
ParameterCategory/Statistics
Normal(n = 12)
Severe(n = 8)
ESRD on CAPDor APD(n = 1)
ESRD on HD or HDF
Treatment Period 1(n = 8)
ESRD on HD or HDF
Treatment Period 2(n = 8)
AUCE,last (h∙mU/mL)
Mean (SD) 2650 (1150) 15200 (25400) 6100 (NA) 4870 (3190) 7370 (4040)
%CV 43.5 167.3 NA 65.4 54.8
Median 2240 3490 6100 4500 8410
Min - Max 1490 – 5650 1030 – 75100 6100 – 6100 666 – 9900 889 – 12600
AUCE,last(baseline corrected) (h∙mU/mL)
Mean (SD) 1580 (1110) 13000 (24600) 5250 (NA) 4210 (3230) 5940 (3810)
%CV 70.3 189.1 NA 76.7 64.1
Median 1390 2510 5250 3430 6050
Min - Max 378 – 4410 420 – 72600 5250 – 5250 416 – 9190 479 – 11100
Emax (mU/mL)
Mean (SD) 170 (128) 337 (324) 470 (NA) 260 (200) 409 (225)
%CV 75.7 96.0 NA 77.0 55.1
Median 135 200 470 201 407
Min - Max 30.8 – 501 38.6 – 750 470 – 470 22.6 – 551 35.0 – 702
Emax–baseline (mU/mL)
Mean (SD) 161 (128) 316 (307) 462 (NA) 253 (201) 386 (224)
%CV 80.0 97.2 NA 79.5 58.1
Median 128 191 462 187 350
Min - Max 20.2 – 491 32.9 – 721 462 – 462 20.5 – 544 31.7 – 692
tmax,EPO (h)
Median 8.00 12.00 8.00 10.0 12.0
Min - Max 6.00 – 8.00 8.00 – 24.0 8.00 – 8.00 8.00 – 12.0 8.00 – 12.0
All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient pharmacodynamic data were available to facilitate derivation of at least 1 pharmacodynamic parameter and for whom the time of dosing on the day of sampling was known.
For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; NA: not applicable.
Source: End-of-Text Table 12.5.2.1
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Table 20 Number and Percentage of Treatment-emergent Adverse Events by Renal Function Group (Safety Analysis Set)
MedDRA v19.0
System Organ Class
Preferred Term
Normal(n = 12)n (%)
Severe(n = 9)n (%)
ESRD on CAPD or
APD(n = 1)n (%)
ESRD on HD or HDFTreatment Period 1(n = 12)n (%)
ESRD on HD or HDFTreatment Period 2(n = 12)n (%)
Overall 8 (66.7) 2 (22.2) 0 4 (33.3) 3 (25.0)
Blood and Lymphatic System Disorders 0 1 (11.1) 0 0 0
Anaemia 0 1 (11.1) 0 0 0
Cardiac Disorders 1 (8.3) 0 0 0 0
Tachycardia 1 (8.3) 0 0 0 0
Gastrointestinal Disorders 2 (16.7) 1 (11.1) 0 3 (25.0) 0
Diarrhoea 1 (8.3) 1 (11.1) 0 2 (16.7) 0
Nausea 0 1 (11.1) 0 1 (8.3) 0
Flatulence 1 (8.3) 0 0 0 0
General Disorders and Administration Site Conditions
0 2 (22.2) 0 1 (8.3) 1 (8.3)
Asthenia 0 0 0 1 (8.3) 1 (8.3)
Pyrexia 0 1 (11.1) 0 0 0
Vessel puncture site haematoma 0 1 (11.1) 0 0 0
Infections and Infestations 2 (16.7) 1 (11.1) 0 0 0
Urinary tract infection 1 (8.3) 1 (11.1) 0 0 0
Nasopharyngitis 1 (8.3) 0 0 0 0
Injury, Poisoning and Procedural Complications
0 0 0 0 1 (8.3)
Skin abrasion 0 0 0 0 1 (8.3)
Traumatic haematoma 0 0 0 0 1 (8.3)
Investigations 1 (8.3) 0 0 0 0
Blood creatine phosphokinase increased 1 (8.3) 0 0 0 0
Musculoskeletal and Connective Tissue Disorders
0 0 0 1 (8.3) 0
Musculoskeletal pain 0 0 0 1 (8.3) 0
Nervous System Disorders 3 (25.0) 1 (11.1) 0 2 (16.7) 1 (8.3)
Headache 3 (25.0) 0 0 2 (16.7) 1 (8.3)
Dizziness 0 1 (11.1) 0 0 0
Psychiatric Disorders 1 (8.3) 0 0 0 0
Bradyphrenia 1 (8.3) 0 0 0 0
Skin and Subcutaneous Tissue Disorders 1 (8.3) 0 0 0 0
Rash maculo-papular 1 (8.3) 0 0 0 0
All enrolled subjects who received at least 1 dose of study drug (roxadustat).
A treatment-emergent adverse event was defined as a newly occurring or worsening adverse event observed after starting administration of study drug up until the end-of-study visit, inclusive.
Sorting order: ascending order by SOC code and ascending order by preferred term code was applied.
Adverse events for ESRD subjects on HD/HDF were assigned to treatment periods according to start date/time of adverse event. Adverse events started in treatment period 1 (with no end date/time or end date/time in treatment period 2) were only assigned to treatment period 1 unless they worsened in treatment period 2.
APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration.
Source: End-of-Text Table 12.6.1.2