Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis.
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.
Yim
Dong-Seok
DS
Center for Drug Development Science, Department of Pharmacology, Box 571441, Georgetown University School of Medicine, Washington, DC 20057-1441, USA.
Zhou
Honghui
H
Buckwalter
Mary
M
Nestorov
Ivan
I
Peck
Carl C
CC
Lee
Howard
H
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*
D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept