Predictive Value of Allometric Scaling for Estimation of Propofol Clearance in Neonates, Infants and Adolescents
Mariska Y.M. Peeters(1), Karel Allegaert(2), Heleen Blussé van Oud-Alblas(3,4), Massimo Cella(5), Dick Tibboel(4), Meindert Danhof(5), Catherijne A.J. Knibbe(1,4,5)
(1)Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands; (2)Neonatal Intensive Care Unit, University Hospitals, Leuven, Belgium; (3)Department of Anesthesiology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; (4)Department of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; (5)Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, the Netherlands
Objectives: For propofol, allometric scaling has been applied successfully for between species (rat-humans) and within-human (children and adults) extrapolations, yielding an allometric scaling factor of 0.78 for clearance [1], which is not significantly different from the 0.75 factor for clearance reported in the literature. In the current study, the predictive value of this allometric equation for estimation of propofol clearance was evaluated in (preterm) neonates, infants and adolescents.
Methods: The predictive value of the allometric equation [1] was evaluated using the following datasets. 1.) 25 (pre)term neonates (2930 (range 680-4030) g, PMA 38 (27-43) weeks, PNA 8 (1-25) days) admitted to the Neonatal Intensive Care Unit who received 3 mg/kg propofol just before removal of the chest tube [2], and 2.) 22 nonventilated infants (aged 10 months (3.8-17.3 months), 8.9 kg (4.8-12.5)), admitted to the Pediatric Intensive Care Unit following craniofacial surgery, who received propofol (2-4 mg·kg-1·h-1) during a median of 12,5 (6.0-18.1) hours [3], and 3.) 14 adolescents (aged 14.7 (9.8-20.1) yrs and 51 (36.6-82) kg), who were anaesthesized with propofol-remifentanil during 6.8 (3.3-7.7) hours. The median percent error of the predictions was calculated according to the equation %error = ((Cli - Clallometric)*100)/ Cli, in which CLi is the individual predicted propofol clearance value based on population pharmacokinetic models of neonates, infants and adolescents, and Clallometric is the predicted propofol clearance value using the allometric equation [1].
Results: The allometric equation systematically overpredicted individual propofol clearances in neonates with a median percent error of -288 (-8466-50)% and systematically underpredicted individual propofol clearances in infants (median percent error of 43 (26-64)%). In adolescents the model performed adequately (median percent error -16 (-46-15)%).
Conclusions: Because of systematic overprediction of propofol clearance in neonates and systematic underprediction in infants, allometric scaling using a fixed factor of 0.75 can not be used for the prediction of clearance in neonates and infants. While allometric scaling has been successfully applied between different species and between adults and adolescents, new approaches are required for young infants and (preterm) neonates.
References:
[1] Knibbe CA et al. Br J Clin Pharmacol. 2005 Jun;59(6):705-11
[2] Allegaert K. et al. Br J Anaesth. 2007 Dec;99(6):864-70
[3] Peeters MY et al. Anesthesiology. 2006 Mar;104(3):466-74