title: Leflunomide for inflammatory arthritis in end-stage renal disease on peritoneal dialysis: a pharmacokinetic and pharmacogenetic study.
abstract: OBJECTIVE
  To study the pharmacokinetics and pharmacogenetics of leflunomide and document its efficacy and safety in the treatment of inflammatory arthritis in a patient with end-stage renal disease (ESRD) who was on peritoneal dialysis.
  
  
  METHODS
  Therapy for a 78-year-old man with ESRD who required peritoneal dialysis was started with leflunomide 10 mg/day for psoriatic arthritis. The dosage was increased to 20 mg/day after 3 months. Monitoring was continued until the patient's unexpected death from myocardial infarction at 8 months. Total and unbound teriflunomide (the active metabolite of leflunomide) concentrations were measured by liquid-chromatography-tandem mass spectrometry. Genotyping for CYP2C19 and ABCG2 polymorphisms, both known to influence teriflunomide pharmacokinetics, was also performed.
  
  
  CONCLUSIONS
  Total concentrations of teriflunomide varied between 5.2 and 23.2 mg/L, while unbound concentrations varied between 0.0306 and 0.1468 mg/L. The unbound fraction varied between 0.367% and 0.71%. Teriflunomide was found in the dialysate at a concentration of 0.0981 mg/L. A single CYP2C19 loss of function allele was present, as was wild-type ABCG2. Leflunomide appeared to be therapeutically effective, as evidenced by a reduction in daily prednisolone dosage from 20 mg to 6mg; the Disease Activity Score in 28 joints (DAS28) was 5.46 at enrollment and 4.03 after 7 months. Health Assessment Questionnaire-Disability Index improved from 0.5 to 0.125 at 7 months. Numerous significant adverse events that were considered unrelated to leflunomide occurred.
  
  
  CONCLUSIONS
  Dose adjustment for leflunomide does not appear to be required in the context of ESRD requiring peritoneal dialysis. We present novel evidence that a small amount of teriflunomide is removed by peritoneal dialysis. This case suggests that leflunomide is safe to use as therapy for inflammatory arthritis despite the presence of ESRD requiring peritoneal dialysis.
authors: Department of Rheumatology, Flinders Medical Centre, Flinders University, South Australia, Australia. pajrusso@gmail.com
authors: Paul A J
authors: PA
authors: Russo
authors: Michael D
authors: MD
authors: Wiese
authors: Malcolm D
authors: MD
authors: Smith
authors: Michael J
authors: MJ
authors: Ahern
authors: Jeffrey A
authors: JA
authors: Barbara
authors: E Michael
authors: EM
authors: Shanahan
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015535:Arthritis, Psoriatic / Q000097:blood / Q000188:drug therapy*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000628:therapy*; D000077339:Leflunomide; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D010530:Peritoneal Dialysis; D020641:Polymorphism, Single Nucleotide
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D007555:Isoxazoles; D009363:Neoplasm Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000077339:Leflunomide