Population pharmacokinetics of the active metabolite of leflunomide in pediatric subjects with polyarticular course juvenile rheumatoid arthritis

J Pharmacokinet Pharmacodyn. 2005 Aug;32(3-4):419-39. doi: 10.1007/s10928-005-0049-8.

Abstract

Leflunomide is a pyrimidine synthesis inhibitor used in the treatment of rheumatoid arthritis. Data from two clinical studies were used to establish a population pharmacokinetic (PPK) model for the active metabolite (M1) of leflunomide in patients with juvenile rheumatoid arthritis (JRA) and determine appropriate pediatric doses. Seventy-three subjects 3-17 years of age provided 674 M1 concentrations. The PPK model was derived from nonlinear mixed-effects modeling and qualified by cross-study evaluation and predictive check. A one-compartment model with first-order input described M1 PPK well. Body weight (WT) correlated weakly with oral clearance (CL/F = 0.020.[WT/40](0.430)) and strongly with volume of distribution (V/F = 5.8.[WT/40](0.769)). Steady-state concentrations (C(ss)) of M1 in JRA were compared for a variety of leflunomide dose regimens using Monte-Carlo simulation. To achieve comparable C(ss) values in pediatric patients with JRA to that in adult patients, doses of leflunomide should be adjusted modestly: 10 mg/d for 10-20 kg, 15 mg/d for 20-40 kg, and 20 mg/d for > 40 kg.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / pharmacokinetics*
  • Arthritis, Juvenile / metabolism*
  • Body Weight
  • Child
  • Child, Preschool
  • Drug Administration Schedule
  • Female
  • Humans
  • Isoxazoles / administration & dosage
  • Isoxazoles / pharmacokinetics*
  • Leflunomide
  • Male
  • Models, Biological
  • Monte Carlo Method
  • Randomized Controlled Trials as Topic

Substances

  • Antirheumatic Agents
  • Isoxazoles
  • Leflunomide