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.
Shi
Jun
J
Global Biopharmaceutics, Drug Metabolism and Pharmacokinetics, Aventis Pharmaceuticals, Bridgewater, NJ, USA. jun.shi@FRX.com
Kovacs
Steven J
SJ
Wang
Yaning
Y
Ludden
Thomas M
TM
Bhargava
Vijay O
VO
D000293:Adolescent; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001171:Arthritis, Juvenile / Q000378:metabolism*; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077339:Leflunomide; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D016032:Randomized Controlled Trials as Topic
D018501:Antirheumatic Agents; D007555:Isoxazoles; D000077339:Leflunomide