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

被引:17
|
作者
Shi, J [1 ]
Kovacs, SJ
Wang, YN
Ludden, TM
Bhargava, VO
机构
[1] Aventis Pharmaceut, Global Biopharmaceut Drug Metab & Pharmacokinet, Bridgewater, NJ 08807 USA
[2] Aventis Pharmaceut, US Med Res, Clin Pharmacol, Bridgewater, NJ USA
[3] GloboMax, Pharmacometr Res & Dev, Hanover, MD USA
[4] Forest Labs Inc, Clin Pharmacol & Drug Dynam, Jersey City, NJ USA
关键词
leflunomide; population pharmacokinetics; juvenile rheumatoid arthritis; pediatrics; NONMEM;
D O I
10.1007/s10928-005-0049-8
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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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页码:419 / 439
页数:21
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