title: Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis.
abstract: This study was performed to estimate the population pharmacokinetic (PK) parameters of etanercept in pediatric juvenile rheumatoid arthritis (JRA) patients and to compare the steady-state time-concentration profiles between etanercept 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly subcutaneous (SC) regimens by clinical trial simulation. To this end, mixed-effect analysis (NONMEM, Version 5.1) was performed using the etanercept PK database consisting of 69 JRA patients (4-17 years). Based on the population PK parameters obtained herein, a Monte Carlo clinical trial simulation experiment was conducted to compare the PK profiles in 200 virtual JRA patients who randomly received either etanercept 0.4 mg/kg SC twice weekly or 0.8 mg/kg once weekly for 12 weeks. The following population PK model could adequately describe etanercept PK profiles for twice-weekly SC dosing of 0.4 mg/kg: CL/F (L/h)=0.0576 (female) or 0.0772 (male) x (body surface area in m2/1.071)1.41, V/F(L)=7.88 x (body weight in kg/30.8). The means +/- standard deviations of simulated trough concentrations for 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly dosing regimens were 1.58 +/- 1.07 mg/L and 1.92 +/- 1.09 mg/L, respectively. Peaks during 0.8-mg/kg once-weekly dosing (2.92 +/- 1.41 mg/L) were only 11% higher than during 0.4 mg/kg twice-weekly dosing (2.62 +/- 1.23 mg/L). In conclusion, the clinical trial simulation confirmed that 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly SC regimens of etanercept are expected to yield overlapping steady-state time-concentration profiles, leading to equivalent clinical outcomes. This has been the basis of the recent Food and Drug Administration approval of the 0.8-mg/kg once-weekly regimen in pediatric patients with JRA.
authors.affiliation: Center for Drug Development Science, Department of Pharmacology, Box 571441, Georgetown University School of Medicine, Washington, DC 20057-1441, USA.
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Yim
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
authors.forename: Mary
authors.initials: M
authors.lastname: Buckwalter
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
authors.forename: Carl C
authors.initials: CC
authors.lastname: Peck
authors.forename: Howard
authors.initials: H
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000378:metabolism*; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D017277:Drug Approval; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D015337:Multicenter Studies as Topic; D010599:Pharmacokinetics; D016032:Randomized Controlled Trials as Topic; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept