Pharmacokinetic and Tolerability Study of 14 mg Single Dose of Teriflunomide in Subjects With Severe Renal Impairment

Primary Objective:

- To determine the effect of severe renal impairment on the pharmacokinetic profile of teriflunomide administered as a single 14 mg dose as compared to healthy subjects

Secondary Objective:

- To assess the tolerability of teriflunomide administered as a single 14 mg dose in subjects with severe renal impairment compared to subjects with normal renal function.

The total study duration per subject is 11-15 weeks broken down as follows:

• Screening: up to 3 weeks
• Hospitalization: 3 days (admission 1 day prior to study drug intake)
• Follow-up: 10 -12 weeks

• Drug: Teriflunomide HMR1726

  Pharmaceutical form:film coated tablet

  Route of administration: oral administration on Day 1 under fasted condition

• Drug: Cholestyramine

  Pharmaceutical form:powder

  Route of administration: oral administration 3 times per day on Day 54 and 55

• Experimental: Severe impaired renal function
  Subjects with severe renal impairment as defined by Cockroft-Gault formula
  Interventions:

  • Drug: Teriflunomide HMR1726
  • Drug: Cholestyramine
• Experimental: Normal renal function
  Subjects with normal renal function as defined by Cockroft-Gault formula
  Interventions:

  • Drug: Teriflunomide HMR1726
  • Drug: Cholestyramine

Inclusion criteria:

Subjects with renal impairment:

• Male subject between 18 and 75 years of age inclusive and postmenopausal female between 45 and 75 years of age inclusive.
• Chronic severe renal impairment as defined by Cockroft-Gault formula (creatinine clearance (CLcr) < 30mL/min, but not requiring hemodialysis).
• Laboratory parameters within the acceptable range for subjects with renal impairment; in particular, hepatic enzymes (ALT, AST) and bilirubin should be < 2 x upper limit of normal range and neutrophils should be within normal ranges.

Matched healthy subjects:

• Male subject between 18 and 75 years of age inclusive and postmenopausal female between 45 and 75 years of age inclusive, matched by age.
• Body weight within 15% of the body weight of the subjects with renal impairment to be matched and Body Mass Index between 18.0 and 30.0 mg/kg2 inclusive.
• Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
• Normal renal function as defined by Cockroft-Gault formula (creatinine clearance (CLcr) > 80mL/min)
• Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy subjects; however serum creatinine, alkaline phosphatase, hepatic enzymes (AST, ALT), bilirubin (unless the subject has documented Gilbert syndrome) should not exceed the upper limit of normal range.

Exclusion criteria:

Subjects with renal impairment:

• Uncontrolled clinically relevant cardiovascular, pulmonary, gastro-intestinal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecologic (if female) or infectious disease, or signs of acute illness.
• Active hepatitis, hepatic insufficiency.
• Acute renal failure (de novo or superimposed to pre-existing chronic renal impairment), nephrotic syndrome.
• Subject requiring dialysis during the study.
• Any significant change in chronic treatment medication within 14-days before inclusion.
• Any drug, which could impact by any mechanism of action, the pharmacokinetic of the investigational product.
• Positive reaction to Human Immunodeficiency Virus (HIV) tests: anti-HIV1 antibodies, anti-HIV2 antibodies
• Positive results on urine drug screen (amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates) unless this result is secondary to a documented medical prescription.
• Positive alcohol test.
• Man who disagrees to use a double barrier method of contraception with their partner during the study.

Matched healthy subjects:

• Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecologic (if female), or infectious disease, or signs of acute illness.

• For subjects 50 years old and below:

  • any medication (including St John's Wort) within 14 days before inclusion, or within 5 times the elimination half-life or pharmacodynamic halflife of that drug, whichever the longest, with the exception of menopausal hormone replacement therapy.
  • any significant change in chronic treatment medication within 14-days before inclusion.
• Any drug, which could impact by any mechanism of action, the pharmacokinetic of the investigational product.
• Positive reaction to any of the following tests: hepatitis B surface (HBs) antigen, antihepatitis C virus (anti-HCV) antibodies, HIV1 antibodies, anti-HIV2 antibodies.
• Positive results on urine drug screen (amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates).
• Positive alcohol test.
• Man who disagrees to use a double barrier method of contraception with their partner during the study

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.