期刊
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
卷 32, 期 3-4, 页码 419-439出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10928-005-0049-8
关键词
leflunomide; population pharmacokinetics; juvenile rheumatoid arthritis; pediatrics; NONMEM
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 center dot[WT/40](0.430)) and strongly with volume of distribution (V/F = 5.8 center dot[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.
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