For subjects with normal renal function or severely impaired renal function, this study will evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma and urine. For subjects with end stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD), this study will evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma, urine and dialysate. For subjects with ESRD on hemodialysis (HD) or hemodiafiltration (HDF), this study will evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma, urine and dialysate and also the effect of dialysis on the pharmacokinetics of roxadustat and its main metabolites.
This is a phase 1, open-label study in two sites. There will be four different renal function groups. For all subjects: Subjects will be allocated to the normal and severely impaired renal function groups based on estimated glomerular filtration rate (eGFR), calculated with the abbreviated modification of diet in renal disease (MDRD) equation. The eGFR will be based on the serum creatinine concentration and is assessed at screening and at day -2. The eGFR obtained at screening will determine the allocation. Subjects will be allocated to the ESRD groups based on their dialysis requirements. Subjects with normal and severely impaired renal function, and subjects with ESRD on CAPD or APD: Screening will take place from day -30 to day -3 and the subjects will be admitted to the clinical unit on day -2. The treatment period lasts 8 days, during which the subjects will receive a single oral dose of roxadustat in the morning of day 1 Subjects will complete the treatment period on day 6, provided that all required assessments have been performed and there are no medical reasons for a prolonged follow-up. The study will be completed with an end-of-study visit (ESV), which will take place between 5 and 9 days after the last treatment period-defined assessment (or after early withdrawal). Subjects with ESRD on HD or HDF: Screening will take place from day -30 to day -3 and subjects will complete 2 treatment periods of 8 days (period 1) and 7 days (period 2) in order to evaluate the pharmacokinetics of roxadustat with a single oral dose of roxadustat on day 1 of both periods after and before dialysis. Subjects will complete the treatment period 1 on day 6 followed by a wash-out period which is minimally 1 week and maximally 3 weeks. Subjects will complete period 2 on day 6, provided that all required assessments have been performed and there are no medical reasons for a prolonged follow-up. The study will be completed with an end-of-study visit (ESV), which will take place between 5 and 9 days after the last treatment period-defined assessment (or after early withdrawal). All subjects: Safety assessments will be performed throughout the study. An optional biobanking sample may be taken for potential exploratory, retrospective, gene polymorphism analysis. Roxadustat plasma, urine, and dialysate samples will be stored for potential exploratory metabolic profiling or exploratory biomarker analysis after the study.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
34
Oral
Site DE49001
München, Germany
Site GB44001
Liverpool, United Kingdom
Pharmacokinetics of Roxadustat in plasma: Cmax
Cmax: Maximum concentration
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: Cmax,u
Cmax,u: Maximum concentration of unbound compound
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: AUCinf
AUCinf: Area under the concentration-time curve from the time of dosing extrapolated to time infinity
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: AUCinf,u
AUCinf,u: Area under the concentration-time curve from the time of dosing extrapolated to time infinity for unbound concentration
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: AUClast
AUClast: Area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast)
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: AUClast,u
AUClast,u: Area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast) for unbound concentration
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: CL/F
CL/F: Apparent total systemic clearance after single or multiple extravascular dosing
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: CLu/F
CLu/F: Apparent total systemic clearance of unbound compound after extravascular dosing
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: fu
fu: Fraction of parent or metabolite available systemically unbound (= free fraction)
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: tmax
tmax: Time of the maximum concentration
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma t1/2
t1/2: Terminal elimination half-life
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: Vz/F
Vz/F: Apparent volume of distribution during the terminal elimination phase after single extravascular dosing
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: Vz,u/F
Vz,u/F: Apparent volume of distribution during the terminal elimination phase of unbound compound after extravascular dosing
Time frame: Up to day 6
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: Cmax
Time frame: Up to day 6
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: AUCinf
Time frame: Up to day 6
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: AUClast
Time frame: Up to day 6
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: tlag
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
Time frame: Up to day 6
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: tmax
Time frame: Up to day 6
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: t1/2
Time frame: Up to day 6
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: MPR
MPR: Metabolite to parent ratio of AUC using AUC (corrected) for the metabolite (corrected by molecular weight ratio of parent to metabolite)
Time frame: Up to day 6
Pharmacokinetics of O-glucoside -Roxadustat in plasma: Cmax
Time frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: AUCinf
Time frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: AUClast
Time frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: tlag
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
Time frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: tmax
Time frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: t1/2
Time frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: MPR
MPR: Metabolite to parent ratio of AUC using AUC(corrected) for the metabolite (corrected by molecular weight ratio of parent to metabolite)
Time frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: Cmax
Time frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: AUCinf
Time frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: AUClast
Time frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: tlag
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
Time frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: tmax
Time frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: t1/2
Time frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: MPR
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in urine: CLR
CLR: Renal clearance
Time frame: Up to day 4
Pharmacokinetics of Roxadustat in urine: CLR,u
CLR,u: Renal clearance of unbound drug
Time frame: Up to day 4
Pharmacokinetics of Roxadustat in urine: Aeinf
Aeinf: Cumulative amount of compound excreted into urine from time of dosing extrapolated to time infinity
Time frame: Up to day 4
Pharmacokinetics of Roxadustat in urine: Aeinf%
Aeinf%: Percent of drug dose excreted into urine (Aeinf) from time of dosing extrapolated to time infinity
Time frame: Up to day 4
Pharmacokinetics of Roxadustat in urine: Aelast
Aelast: Cumulative amount of drug excreted into urine from time of dosing up to the collection time of the last measurable concentration
Time frame: Up to day 4
Pharmacokinetics of Roxadustat in urine: Aelast%
Aelast%: Percent of drug dose excreted into urine (Aelast) from time of dosing up to the collection time of the last measurable concentration
Time frame: Up to day 4
Pharmacokinetics of O-glucuronide-Roxadustat in urine: CLR
Time frame: Up to day 4
Pharmacokinetics of O-glucuronide-Roxadustat in urine: Aeinf
Time frame: Up to day 4
Pharmacokinetics of O-glucuronide-Roxadustat in urine: Aelast
Time frame: Up to day 4
Pharmacokinetics of O-glucuronide-Roxadustat in urine: MPR based on Aeinf
Time frame: Up to day 4
Pharmacokinetics of O-glucoside-Roxadustat in urine: CLR
Time frame: Up to day 4
Pharmacokinetics of O-glucoside-Roxadustat in urine: Aeinf
Time frame: Up to day 4
Pharmacokinetics of O-glucoside-Roxadustat in urine: Aelast
Time frame: Up to day 4
Pharmacokinetics of O-glucoside-Roxadustat in urine: MPR based on Aeinf
Time frame: Up to day 4
Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: CLR
Time frame: Up to day 4
Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: Aeinf
Time frame: Up to day 4
Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: Aelast
Time frame: Up to day 4
Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: MPR based on Aeinf
Time frame: Up to day 4
Pharmacokinetics of Roxadustat and its main metabolites in dialysate fluid: CLD
CLD: dialysis clearance. For ESRD subjects on CAPD or APD and for ESRD subjects on HD or HDF (treatment period 2 only)
Time frame: Up to day 2
Pharmacokinetics of Roxadustat in dialysate fluid: fD
fD: fraction of dose cleared by dialysis. For ESRD subjects on CAPD or APD and for ESRD subjects on HD or HDF (treatment period 2 only)
Time frame: Up to day 2
Pharmacokinetics of O-glucuronide-Roxadustat in urine: Aeinf%
Time frame: Up to day 4
Pharmacokinetics of O-glucoside-Roxadustat in urine: Aeinf%
Time frame: Up to day 4
Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: Aeinf%
Time frame: Up to day 4
Pharmacokinetics of Roxadustat in plasma: Effective t½ 48 hours
Effective t½ 48 hours: Effective half-life based on a dosing interval of 48 hours
Time frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: Effective t½ 56 hours
Effective t½ 56 hours: Effective half-life based on a dosing interval of 56 hours
Time frame: Up to day 6
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: TER
TER: Total exposure ratio
Time frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: TER
Time frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: TER
Time frame: Up to day 6
Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): Emax
Emax: Maximum effect
Time frame: Up to day 6
Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): Emax-baseline
Emax-baseline: Maximum effect from baseline
Time frame: U to day 6
Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): AUCE,last
AUCE,last: Area under the effect-time curve from the time of dosing to the last measurable effect
Time frame: Up to day 6
Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): AUCE,last (baseline-corrected)
AUCE,last (baseline-corrected): Area under the effect-time curve from the time of dosing to the last measurable effect baseline corrected
Time frame: Up to day 6
Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): tmax, EPO
tmax, EPO: Time to maximum EPO concentration
Time frame: Up to day 6
Safety assessed by nature, frequency, and severity of Adverse Events (AEs)
Time frame: Up to End of Study (EOS) (Up to day 15, period 2)
Number of participants with vital signs abnormalities and/or adverse events related to treatment
Vital signs include: blood pressure (systolic and diastolic) and pulse
Time frame: Up to EOS (Up to day 15, period 2)
Safety assessed by routine 12- lead electrocardiogram (ECG)
Routine 12-lead ECG measurements will be performed for the different renal function groups, as applicable, after the subject has been in a supine position for at least 5 minutes. All routine 12-lead ECG data will be listed by subject
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: Up to EOS (Up to day 15, period 2)
Safety assessed by continuous heart rate (HR) measurement
Holter
Time frame: Up to day 2 (period 1)
Number of participants with laboratory value abnormalities and/or adverse events related to treatment
Safety laboratory tests include: hematology, biochemistry and urinalysis
Time frame: Up to EOS (Up to day 15, period 2)