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Clonidine disposition in children: a population analysis
Author(s) -
Potts AL,
Larsson P,
Eksborg S,
Warman G,
Lönnqvist PA,
Anderson BJ
Publication year - 2007
Publication title -
pediatric anesthesia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.704
H-Index - 82
eISSN - 1460-9592
pISSN - 1155-5645
DOI - 10.1111/j.1460-9592.2007.02255_6.x
Subject(s) - medicine , volume of distribution , pharmacokinetics , clonidine , population , bolus (digestion) , cmax , disposition , anesthesia , dosing , surgery , psychology , social psychology , environmental health
Background: There are few data describing clonidine population pharmacokinetics in children (0–15 years) despite common use. Current paediatric data, described in terms of elimination half‐life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically. Methods: Published data from four studies investigating clonidine PK after intravenous, rectal and epidural administration ( n = 42) were combined with an open‐label study undertaken to examine the pharmacokinetics of IV clonidine 1–2 μg·kg −1 bolus in children after cardiac surgery ( n = 30, EC approval granted). A population pharmacokinetic analysis of clonidine time‐concentration profiles (380 observations) was undertaken using nonlinear mixed effects modelling. Estimates were standardised to a 70 kg adult using allometric size models. Results: Children had a mean age of four (SD 3.6 years, range 1 week–14 years) year and weight 17.8 (SD 12.6, range 2.8–60 kg). A two compartment disposition model with first order elimination was superior to a one compartment model. Population parameter estimates (between subject variability) were clearance (CL) 14 (CV 28.3%) 1 h –1 ·70 kg −1 , central volume of distribution (V1) 56.7 (67.5%) l·70 kg −1 , inter‐compartment clearance (Q) 143 (19.1%) l h –1 70 kg −1 and peripheral volume of distribution (V2) 123 (72.8%) l.70kg −1 . Clearance at birth was 4.7 l·h –1· 70kg −1 and matured with a half‐time of 25.5 weeks to reach 85% adult rate by 1 year of age. The volumes of distribution, but not clearance, were increased after cardiac surgery (V1 180%, V2 117%). There was a lag time of 2.6 (CV 64%) min before absorption began in the rectum. The absorption half‐life from the epidural space was slower than that from the rectum 1.04 (CV31%) h vs 0.28 (CV24%) h. The relative bioavailability of epidural and rectal clonidine was unity ( F = 1). Conclusions: Clearance in neonates is approximately one third that described in adults, consistent with immature clearance pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach.