Pharmacokinetic and pharmacodynamic basis for effective argatroban dosing in pediatrics.
The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of argatroban in pediatric patients and derive dosing recommendations. An open-label multicenter trial was conducted in pediatric patients (n = 18 from birth to 16 years). A population modeling approach was used to characterize pharmacokinetics and pharmacodynamics of argatroban in pediatric patients. Simulations were performed to derive a dosing regimen for pediatric patients. The estimated clearance of argatroban in pediatric patients was 2-fold lower than that in healthy adults. Body weight was significant predictor of argatroban clearance. The clearance in a typical 20-kg pediatric patient was 3.1 L/h. In 4 patients with elevated serum bilirubin levels, the estimated clearance was 0.6 L/h. Effect on activated plasma thromboplastin time (aPTT) was found to be concentration dependent. Simulations suggested that a starting dose of 0.75 µg/kg/min in pediatric patients was comparable in performance to 2.0 µg/kg/min approved in adults for attaining target aPTT and risk for bleeding. A dose increment step size of 0.25 µg/kg/min was suitable for titration. The PK/PD of argatroban was reasonably characterized in pediatrics. Plasma concentration-aPTT relationship was used to derive a safe starting dose and titration scheme for the first time in pediatric patients and was incorporated into the US prescribing information for argatroban.
Madabushi
Rajanikanth
R
Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002, USA. Rajnikanth.Madabushi@fda.hhs.gov
Cox
Donna S
DS
Hossain
Mohammad
M
Boyle
Duane A
DA
Patel
Bela R
BR
Young
Guy
G
Choi
Young-Moon
YM
Gobburu
Jogarao V S
JV
D000293:Adolescent; D001120:Arginine / Q000031:analogs & derivatives; D001663:Bilirubin / Q000097:blood; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D010314:Partial Thromboplastin Time; D010875:Pipecolic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D013449:Sulfonamides
D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban; D001663:Bilirubin