A Phase 1 Study of Roxadustat in Subjects With Different Degrees of Renal Function

NCT02965040 | Completed Phase 1

• 2 other identifiers: 1517-CL-05432015-002565-28
• Study Type: interventional
• Target: 34
• Locations: 2 countries
• Sites: 2

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.

Conditions

Normal Renal Function; Impaired Renal Function

Keywords

ASP1517; Normal renal function; Dialysis; Roxadustat; Metabolites; Pharmacokinetics; Impaired renal function

Outcome Measures

Primary Outcomes (62)

• Pharmacokinetics of Roxadustat in plasma: Cmax

  Cmax: Maximum concentration

  Up to day 6

• Pharmacokinetics of Roxadustat in plasma: Cmax,u

  Cmax,u: Maximum concentration of unbound compound

  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

  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

  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)

  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

  Up to day 6

• Pharmacokinetics of Roxadustat in plasma: CL/F

  CL/F: Apparent total systemic clearance after single or multiple extravascular dosing

  Up to day 6

• Pharmacokinetics of Roxadustat in plasma: CLu/F

  CLu/F: Apparent total systemic clearance of unbound compound after extravascular dosing

  Up to day 6

• Pharmacokinetics of Roxadustat in plasma: fu

  fu: Fraction of parent or metabolite available systemically unbound (= free fraction)

  Up to day 6

• Pharmacokinetics of Roxadustat in plasma: tmax

  tmax: Time of the maximum concentration

  Up to day 6

• Pharmacokinetics of Roxadustat in plasma t1/2

  t1/2: Terminal elimination half-life

  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

  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

  Up to day 6

• Pharmacokinetics of O-glucuronide-Roxadustat in plasma: Cmax

  Up to day 6

• Pharmacokinetics of O-glucuronide-Roxadustat in plasma: AUCinf

  Up to day 6

• Pharmacokinetics of O-glucuronide-Roxadustat in plasma: AUClast

  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

  Up to day 6

• Pharmacokinetics of O-glucuronide-Roxadustat in plasma: tmax

  Up to day 6

• Pharmacokinetics of O-glucuronide-Roxadustat in plasma: t1/2

  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)

  Up to day 6

• Pharmacokinetics of O-glucoside -Roxadustat in plasma: Cmax

  Up to day 6

• Pharmacokinetics of O-glucoside-Roxadustat in plasma: AUCinf

  Up to day 6

• Pharmacokinetics of O-glucoside-Roxadustat in plasma: AUClast

  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

  Up to day 6

• Pharmacokinetics of O-glucoside-Roxadustat in plasma: tmax

  Up to day 6

• Pharmacokinetics of O-glucoside-Roxadustat in plasma: t1/2

  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)

  Up to day 6

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: Cmax

  Up to day 6

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: AUCinf

  Up to day 6

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: AUClast

  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

  Up to day 6

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: tmax

  Up to day 6

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: t1/2

  Up to day 6

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: MPR

  Up to day 6

• Pharmacokinetics of Roxadustat in urine: CLR

  CLR: Renal clearance

  Up to day 4

• Pharmacokinetics of Roxadustat in urine: CLR,u

  CLR,u: Renal clearance of unbound drug

  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

  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

  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

  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

  Up to day 4

• Pharmacokinetics of O-glucuronide-Roxadustat in urine: CLR

  Up to day 4

• Pharmacokinetics of O-glucuronide-Roxadustat in urine: Aeinf

  Up to day 4

• Pharmacokinetics of O-glucuronide-Roxadustat in urine: Aelast

  Up to day 4

• Pharmacokinetics of O-glucuronide-Roxadustat in urine: MPR based on Aeinf

  Up to day 4

• Pharmacokinetics of O-glucoside-Roxadustat in urine: CLR

  Up to day 4

• Pharmacokinetics of O-glucoside-Roxadustat in urine: Aeinf

  Up to day 4

• Pharmacokinetics of O-glucoside-Roxadustat in urine: Aelast

  Up to day 4

• Pharmacokinetics of O-glucoside-Roxadustat in urine: MPR based on Aeinf

  Up to day 4

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: CLR

  Up to day 4

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: Aeinf

  Up to day 4

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: Aelast

  Up to day 4

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: MPR based on Aeinf

  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)

  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)

  Up to day 2

• Pharmacokinetics of O-glucuronide-Roxadustat in urine: Aeinf%

  Up to day 4

• Pharmacokinetics of O-glucoside-Roxadustat in urine: Aeinf%

  Up to day 4

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in urine: Aeinf%

  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

  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

  Up to day 6

• Pharmacokinetics of O-glucuronide-Roxadustat in plasma: TER

  TER: Total exposure ratio

  Up to day 6

• Pharmacokinetics of O-glucoside-Roxadustat in plasma: TER

  Up to day 6

• Pharmacokinetics of sulfate of hydroxy-Roxadustat in plasma: TER

  Up to day 6

Secondary Outcomes (10)

• Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): Emax

  Up to day 6

• Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): Emax-baseline

  U to day 6

• Pharmacodynamics of Roxadustat assessed by measuring erythropoietin (EPO): AUCE,last

  Up to day 6

• 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

Study Arms (4)

Roxadustat: subjects with normal renal function

EXPERIMENTAL

Normal renal function: eGFR is equal to or greater than 90 mL/min/1.73 m\^2. Single dose of roxadustat

Drug: Roxadustat

Roxadustat: subjects with severely impaired renal function

EXPERIMENTAL

Severely impaired renal function: eGFR is less than 30 mL/min/1.73 m\^2. Single dose of roxadustat

Drug: Roxadustat

Roxadustat: subjects with ESRD on CAPD or APD

EXPERIMENTAL

ESRD subjects on CAPD or APD need to be on the same mode of dialysis for at least 4 months. Single dose of roxadustat

Drug: Roxadustat

Roxadustat: subjects with ESRD on HD or HDF

EXPERIMENTAL

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

Drug: Roxadustat

Interventions

Roxadustat DRUG

Oral

Also known as: FG-4592, ASP1517

Roxadustat: subjects with ESRD on CAPD or APD; Roxadustat: subjects with ESRD on HD or HDF; Roxadustat: subjects with normal renal function; Roxadustat: subjects with severely impaired renal function

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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\^2.
• 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.
• Subject is a male or female subject aged 18 to 75 years, inclusive.
• Subject is on CAPD or APD treatment with the same mode of dialysis for at least 4 months prior to admission to the clinical unit.
• Subject is a male or female subject aged 18 to 75 years, inclusive.
• Subject is 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 dialysis sessions three times weekly.
• If a subject is being treated with short-acting ESAs, the subject agrees to discontinue treatment for at least 14 days prior to admission.

You may not qualify if:

• 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 -2.
• 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.
• Subject has a positive serology test for hepatitis B surface antigen (HBsAg), anti-hepatitis A virus (immunoglobulin M \[IgM\]), anti-hepatitis C virus, hepatitis B core antibody or anti-human immunodeficiency virus (HIV) type 1 or 2 \[screening\].
• Subject participated in any clinical study or has been treated with any investigational drugs within 28 days (or 5 half-lives whichever is longer), prior to screening.
• Subject has any condition which makes the subject unsuitable for clinical study participation.
• Subject is a vulnerable subject (e.g., subject kept in detention).
• Subjects aged greater than or equal to 40 and \< 65:
• Subject has a mean pulse \< 45 or \>90 bpm; mean systolic blood pressure \<90 mmHg and \>140 mmHg; mean diastolic blood pressure \<50 mmHg and \>90 mmHg at day -2. Vital signs measurements taken in triplicate after subject has been resting in supine position for 5 minutes; pulse will be measured automatically. If the mean pulse, systolic blood pressure or diastolic blood pressure exceeds the limits above, 1 additional triplicate can be taken \[day -2\].

Sponsors & Collaborators

• Astellas Pharma Europe B.V.: lead
• Kyntra Bio: collaborator

Study Sites (2)

Site DE49001

München, 81241, Germany

Location

Site GB44001

Liverpool, L7 8XP, United Kingdom

Location

Related Publications (1)

• Groenendaal-van de Meent D, Kerbusch V, Kaspera R, Barroso-Fernandez B, Galletti P, Klein GK, den Adel M. Effect of Kidney Function and Dialysis on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor. Eur J Drug Metab Pharmacokinet. 2021 Jan;46(1):141-153. doi: 10.1007/s13318-020-00658-w.

  PMID: 33165773 DERIVED

Related Links

• Link to results on Astellas Clinical Study Results website

MeSH Terms

Conditions

Renal Insufficiency

Interventions

roxadustat

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Study Officials

• Medical Monitor

  Astellas Pharma Europe B.V.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 11, 2016
• First Posted: November 16, 2016
• Study Start: December 12, 2016
• Primary Completion: December 4, 2017
• Study Completion: December 11, 2017
• Last Updated: February 12, 2020

Record last verified: 2020-02

Locations

GB (1); DE (1)