Population pharmacokinetics of oxycodone: Premature neonates to adults.

Abstract

Oxycodone is used in children and adults for the control of acute postoperative pain. Covariate influences such as age, size, and fat mass on oxycodone pharmacokinetic parameters over the human lifespan are poorly quantified. Pooled oxycodone time-concentration profiles were available from preterm neonates to adults. Data from intravenous, intramuscular, buccal, and epidural formulations were analyzed using nonlinear mixed-effects models. Normal fat mass was used to determine the influence of fat on oxycodone pharmacokinetics. Theory-based allometry was used to scale pharmacokinetic parameters to a 70kg individual. A maturation function described the increase in clearance in neonates and infants. There were 237subjects (24weeks postmenstrual age to 75years; 0.44-110kg) providing 1317 plasma concentrations. A three-compartment model with first-order elimination best described oxycodone disposition. Population parameter estimates were clearance (CL) 48.6 L.h-1 .70kg-1 (CV 71%); intercompartmental clearances (Q2) 220 L.h-1 .70kg-1 (CV 64%); Q3 1.45 L.h-1 .70kg-1 ; volume of distribution in the central compartment (V1) 98.2 L.70kg-1 (CV 76%); rapidly equilibrating peripheral compartment (V2) 90.1 L. 70kg-1 (CV 76%); slow equilibrating peripheral compartment (V3) 28.9 L.70kg-1 . Total body weight was the best size descriptor for clearances and volumes. Absorption halftimes (TABS ) were: 1.1minutes for intramuscular, 70minutes for epidural, 82minutes for nasogastric, and 159.6minutes for buccal administration routes. The relative bioavailability after nasogastric administration was 0.673 with a lag time of 8.7minutes. Clearance matured with age; 8% of the typical adult value at 24weeks postmenstrual age, 33% in a term neonate and reached 90% of the adult clearance value by the end of the first year of life. Allometric scaling using total body weight was the better size descriptor of oxycodone clearance than fat-free mass.