Population pharmacokinetics (PPK) analysis of A77 1726 (M1) after oral administration of leflunomide (LEF) in pediatric subjects with polyarticular course juvenile rheumatoid arthritis (JRA)

Purpose Establish a PPK model describing the PK characteristics of the active metabolite (M1) of LEF in JRA; examine the influence of demographic covariates on PK of M1 in JRA; determine appropriate pediatric dose adjustments. Methods : S1037: 24‐wk open‐label trial, subjects 6–17 yrs; LEF dosing based on 10 mg/d per 1.73 m 2 . Serial blood samples (5) collected on d 3, wks 4, 12, 26. S3503: 16‐wk double‐blind trial, subjects 3‐17 yrs; LEF dosing by body weight (WT): 5 mg qd <20 kg; 10 mg qd 20‐40 kg; 20 mg qd >40 kg. Single blood samples collected at wks 2, 4, 8, 12, 16. Bioanalysis for M1 by HPLC/UV, LOQ 0.1 μg/mL. Data pooled; population analysis by NONMEM; dose adjustments tested by simulation. Results : 73 subjects 3–17 yrs (S1037 n=27; S3503 n=46) provided 674 M1 observations. M1 disposition was well described by a one‐compartment model with first order input. CL/F was weakly correlated with body size (WT or BSA): CL/F=0.020[WT/40] 0.43 . V/F was strongly correlated with body size: V/F=5.8[WT/40] 0.769 . Inter‐subject variabilities in CL/F and V/F were 50.4% and 18.6% and similar to adults. In S3503 20 mg qd in subjects >40 kg achieved C ss (36.7 μg/mL) comparable to adults (34 μg/mL). C ss in pts <20 kg or 20–40 kg were low (12.6 μg/mL; 26.2 μg/mL, resp). Conclusions : To achieve a uniform range of C ss within the JRA population and comparable to adults, LEF doses should be adjusted for WT: 10 mg qd 10–19.9 kg; 15 mg qd 20–40 kg (20 mg/10 mg alternate days); 20 mg qd >40 kg. Clinical Pharmacology & Therapeutics (2004) 75 , P5–P5; doi: 10.1016/j.clpt.2003.11.017