A Phase 1 Study to Evaluate the Pharmacokinetics of Roxadustat in Subjects With Different Degrees of Renal Function
Overview
- Phase
- Phase 1
- Intervention
- Roxadustat
- Conditions
- Normal Renal Function
- Sponsor
- Astellas Pharma Europe B.V.
- Enrollment
- 34
- Locations
- 2
- Primary Endpoint
- Pharmacokinetics of O-glucoside-Roxadustat in plasma: TER
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Inclusion criteria for all subjects:
- •Subject has a body weight of 45 to 160 kg, inclusive.
- •For subjects with ESRD on CAPD or APD body weight should be recorded as the measured body weight minus abdominal dialysis fluid based on the last filling. For subjects with ESRD on HD or HDF the post-dialysis body weight will be recorded.
- •Specific inclusion criteria for subjects with normal renal function:
- •Subject is a healthy male or female subject aged 40 to 75 years, inclusive.
- •Subject must have a pre-dose eGFR value based on the abbreviated MDRD method of greater than or equal to 90 mL/min/1.73 m\^
- •Specific inclusion criteria for subjects with severely impaired renal function:
- •Subject is a male or female subject aged 18 to 75 years, inclusive.
- •Subject must have a pre-dose eGFR value based on the abbreviated MDRD method \[screening\] of \<30 mL/min/1.73 m\^2 and not be on dialysis.
- •Specific inclusion criteria for subjects with ESRD on CAPD or APD:
Exclusion Criteria
- •Exclusion criteria for all subjects:
- •Subject has a known or suspected hypersensitivity to Roxadustat or any components (e.g., lactose) of the formulations used.
- •Subject has any clinically significant history of allergic conditions (including drug allergies or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
- •Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (noncutaneous) infection within 1 week prior to admission to the clinical unit.
- •Subject has any clinically significant abnormality following the investigator's review of the physical examination, electrocardiogram (ECG), and clinical study protocol-defined clinical laboratory tests at screening or day -
- •Subject has a history of smoking more than 10 cigarettes (or equivalent amount of tobacco) per day within 3 months prior to admission to the clinical unit.
- •Subject has a history of drinking more than 21 units (male subjects) or more than 14 units (female subjects) of alcohol per week (1 unit = 10 g pure alcohol = 250 mL of beer \[5%\] or 35 mL of spirits \[35%\] or 100 mL of wine \[12%\]) within 3 months prior to admission to the clinical unit.
- •Subject uses moderate or strong inducers of metabolism (e.g., barbiturates, rifampin) regularly in the 1 month prior to admission to the clinical unit.
- •Subject must not consume grapefruit (or any grapefruit-containing products, including juice) or Seville oranges (or any Seville orange-containing products, including juice) within 7 days prior to admission to the clinical unit.
- •Subject uses any drugs of abuse within 3 months prior to admission to the clinical unit.
Arms & Interventions
Roxadustat: subjects with normal renal function
Normal renal function: eGFR is equal to or greater than 90 mL/min/1.73 m\^2. Single dose of roxadustat
Intervention: Roxadustat
Roxadustat: subjects with severely impaired renal function
Severely impaired renal function: eGFR is less than 30 mL/min/1.73 m\^2. Single dose of roxadustat
Intervention: Roxadustat
Roxadustat: subjects with ESRD on CAPD or APD
ESRD subjects on CAPD or APD need to be on the same mode of dialysis for at least 4 months. Single dose of roxadustat
Intervention: Roxadustat
Roxadustat: subjects with ESRD on HD or HDF
ESRD subjects on HD or HDF need to be on the same mode of dialysis for at least 4 months and should have dialysis sessions three times weekly. Single dose of roxadustat, in both treatment periods
Intervention: Roxadustat
Outcomes
Primary Outcomes
Pharmacokinetics of O-glucoside-Roxadustat in plasma: TER
Time Frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: AUCinf,u
Time Frame: Up to day 6
AUCinf,u: Area under the concentration-time curve from the time of dosing extrapolated to time infinity for unbound concentration
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: AUClast
Time Frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: Vz,u/F
Time Frame: Up to day 6
Vz,u/F: Apparent volume of distribution during the terminal elimination phase of unbound compound after extravascular dosing
Pharmacokinetics of Roxadustat in plasma: Cmax
Time Frame: Up to day 6
Cmax: Maximum concentration
Pharmacokinetics of Roxadustat in plasma: Cmax,u
Time Frame: Up to day 6
Cmax,u: Maximum concentration of unbound compound
Pharmacokinetics of Roxadustat in plasma: AUCinf
Time Frame: Up to day 6
AUCinf: Area under the concentration-time curve from the time of dosing extrapolated to time infinity
Pharmacokinetics of Roxadustat in plasma: CLu/F
Time Frame: Up to day 6
CLu/F: Apparent total systemic clearance of unbound compound after extravascular dosing
Pharmacokinetics of Roxadustat in plasma: tmax
Time Frame: Up to day 6
tmax: Time of the maximum concentration
Pharmacokinetics of Roxadustat in plasma: Vz/F
Time Frame: Up to day 6
Vz/F: Apparent volume of distribution during the terminal elimination phase after single extravascular dosing
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: tlag
Time Frame: Up to day 6
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
Pharmacokinetics of O-glucoside -Roxadustat in plasma: Cmax
Time Frame: Up to day 6
Pharmacokinetics of Roxadustat in plasma: AUClast
Time Frame: Up to day 6
AUClast: Area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast)
Pharmacokinetics of Roxadustat in plasma: AUClast,u
Time Frame: Up to day 6
AUClast,u: Area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast) for unbound concentration
Pharmacokinetics of Roxadustat in plasma: CL/F
Time Frame: Up to day 6
CL/F: Apparent total systemic clearance after single or multiple extravascular dosing
Pharmacokinetics of Roxadustat in plasma: fu
Time Frame: Up to day 6
fu: Fraction of parent or metabolite available systemically unbound (= free fraction)
Pharmacokinetics of Roxadustat in plasma t1/2
Time Frame: Up to day 6
t1/2: Terminal elimination half-life
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: 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
Time Frame: Up to day 6
MPR: Metabolite to parent ratio of AUC using AUC (corrected) for the metabolite (corrected by molecular weight ratio of parent to metabolite)
Pharmacokinetics of O-glucoside-Roxadustat in plasma: MPR
Time Frame: Up to day 6
MPR: Metabolite to parent ratio of AUC using AUC(corrected) for the metabolite (corrected by molecular weight ratio of parent to metabolite)
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: Cmax
Time Frame: Up to day 6
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: tmax
Time Frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: AUCinf
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: tlag
Time Frame: Up to day 6
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: t1/2
Time Frame: Up to day 6
Pharmacokinetics of Roxadustat in urine: CLR
Time Frame: Up to day 4
CLR: Renal clearance
Pharmacokinetics of O-glucoside-Roxadustat in urine: Aelast
Time Frame: Up to day 4
Pharmacokinetics of O-glucoside-Roxadustat in plasma: AUClast
Time Frame: Up to day 6
Pharmacokinetics of O-glucoside-Roxadustat in plasma: tlag
Time Frame: Up to day 6
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
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 sulfate of hydroxy-Roxadustat in plasma: MPR
Time Frame: Up to day 6
Pharmacokinetics of Roxadustat in urine: CLR,u
Time Frame: Up to day 4
CLR,u: Renal clearance of unbound drug
Pharmacokinetics of Roxadustat in urine: Aelast
Time Frame: Up to day 4
Aelast: Cumulative amount of drug excreted into urine from time of dosing up to the collection time of the last measurable concentration
Pharmacokinetics of Roxadustat in plasma: Effective t½ 56 hours
Time Frame: Up to day 6
Effective t½ 56 hours: Effective half-life based on a dosing interval of 56 hours
Pharmacokinetics of Roxadustat in urine: Aeinf
Time Frame: Up to day 4
Aeinf: Cumulative amount of compound excreted into urine from time of dosing extrapolated to time infinity
Pharmacokinetics of Roxadustat in urine: Aeinf%
Time Frame: Up to day 4
Aeinf%: Percent of drug dose excreted into urine (Aeinf) from time of dosing extrapolated to time infinity
Pharmacokinetics of Roxadustat in urine: Aelast%
Time Frame: Up to day 4
Aelast%: Percent of drug dose excreted into urine (Aelast) from time of dosing up to the collection time of the last measurable concentration
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: 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 O-glucoside-Roxadustat in urine: Aeinf%
Time Frame: Up to day 4
Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: TER
Time Frame: Up to day 6
Pharmacokinetics of Roxadustat and its main metabolites in dialysate fluid: CLD
Time Frame: Up to day 2
CLD: dialysis clearance. For ESRD subjects on CAPD or APD and for ESRD subjects on HD or HDF (treatment period 2 only)
Pharmacokinetics of Roxadustat in dialysate fluid: fD
Time Frame: Up to day 2
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)
Pharmacokinetics of O-glucuronide-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
Time Frame: Up to day 6
Effective t½ 48 hours: Effective half-life based on a dosing interval of 48 hours
Pharmacokinetics of O-glucuronide-Roxadustat in plasma: TER
Time Frame: Up to day 6
TER: Total exposure ratio
Secondary Outcomes
- Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): AUCE,last(Up to day 6)
- Safety assessed by nature, frequency, and severity of Adverse Events (AEs)(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(Up to EOS (Up to day 15, period 2))
- Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): Emax-baseline(U to day 6)
- Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): Emax(Up to day 6)
- Safety assessed by continuous heart rate (HR) measurement(Up to day 2 (period 1))
- Number of participants with laboratory value abnormalities and/or adverse events related to treatment(Up to EOS (Up to day 15, period 2))
- Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): AUCE,last (baseline-corrected)(Up to day 6)
- Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): tmax, EPO(Up to day 6)
- Safety assessed by routine 12- lead electrocardiogram (ECG)(Up to EOS (Up to day 15, period 2))