Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery.
BACKGROUND
Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery.


METHODS
Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs.


RESULTS
Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively.


CONCLUSIONS
EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.
Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4399, USA.
P A
PA
Stricker
A F
AF
Zuppa
J E
JE
Fiadjoe
L G
LG
Maxwell
E M
EM
Sussman
E Y
EY
Pruitt
T K
TK
Goebel
M R
MR
Gastonguay
J A
JA
Taylor
S P
SP
Bartlett
M S
MS
Schreiner
D000367:Age Factors; D015119:Aminocaproic Acid / Q000008:administration & dosage / Q000097:blood*; D000933:Antifibrinolytic Agents / Q000008:administration & dosage / Q000097:blood*; D016063:Blood Loss, Surgical; D001803:Blood Transfusion / Q000379:methods; D001835:Body Weight / Q000502:physiology; D019465:Craniofacial Abnormalities / Q000601:surgery*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005440:Fluid Therapy / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008954:Models, Biological
D000933:Antifibrinolytic Agents; D015119:Aminocaproic Acid