Population Pharmacokinetics of the Active Metabolite of Leflunomide in Pediatric Subjects with Polyarticular Course Juvenile Rheumatoid Arthritis

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.