title: Pharmacokinetic and pharmacodynamic basis for effective argatroban dosing in pediatrics.
abstract: 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.
authors.affiliation: 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
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Madabushi
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hossain
authors.forename: Duane A
authors.initials: DA
authors.lastname: Boyle
authors.forename: Bela R
authors.initials: BR
authors.lastname: Patel
authors.forename: Guy
authors.initials: G
authors.lastname: Young
authors.forename: Young-Moon
authors.initials: YM
authors.lastname: Choi
authors.forename: Jogarao V S
authors.initials: JV
authors.lastname: Gobburu
mesh_terms: 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
chemical_list: D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban; D001663:Bilirubin