Clonidine disposition in children; a population analysis

Abstract

Summary Background: There are few data describing clonidine population pharmacokinetics in children (0–15 years) despite common use. Current pediatric data, described in terms of elimination half‐life or C max and T max , 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 (i.v.), rectal and epidural administration ( n = 42) were combined with an open‐label study undertaken to examine the pharmacokinetics of i.v. clonidine 1–2 μg·kg −1 bolus in children after cardiac surgery ( n = 41). A population pharmacokinetic analysis of clonidine time–concentration profiles (380 observations) was undertaken using nonlinear mixed effects modeling. Estimates were standardized to a 70‐kg adult using allometric size models. Results: Children had a mean age of 4 ( sd 3.6 years, range 1 week–14 years) years 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) 14.6 (CV 35.1%) l·h −1 70 kg −1 , central volume of distribution (V1) 62.5 (71.1%) l 70 kg −1 , intercompartment clearance (Q) 157 (77.3%) l·h −1 70 kg −1 and peripheral volume of distribution (V2) 119 (22.9%) l 70 kg −1 . Clearance at birth was 3.8 l·h −1 70 kg −1 and matured with a half‐time of 25.7 weeks to reach 82% adult rate by 1 year of age. The volumes of distribution, but not clearance, were increased after cardiac surgery (V1 123%, V2 126%). There was a lag time of 2.3 (CV 73.2%) min before absorption began in the rectum. The absorption half‐life from the epidural space was slower than that from the rectum (0.98 CV 24.5% h vs 0.26 CV 32.3% 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 elimination pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach.