Allometric relationships between the pharmacokinetics of propofol in rats, children and adults.
OBJECTIVE
Allometric equations have proven useful for the extrapolation of animal data to determine pharmacokinetic parameters in man. It has been proposed that these equations are also applicable over the human size range including the paediatric population. The aim of this work was to study the relationship between various pharmacokinetic parameters for propofol and body weight using data from rats, children and adults. Furthermore, the utility of allometric scaling is evaluated by the prediction of propofol concentrations in humans based on data obtained in the rat.


METHODS
The relationship between the pharmacokinetic parameters of propofol obtained in rats, children and adults was analyzed by plotting the logarithmically transformed parameters against the corresponding logarithmically transformed body weights. In addition, based on allometric equations, pharmacokinetic parameters obtained in rats were scaled to humans. These parameters were used to simulate propofol concentrations in long-term sedated critically ill patients using NONMEM. Simulated concentrations were then compared with actually observed concentrations in humans.


RESULTS
The relationship between pharmacokinetic parameters of propofol from rats, children and adults was in good agreement with those from the literature on allometric modelling. For clearance, intercompartmental clearance, central volume of distribution and peripheral volume of distribution, the power parameters were 0.78, 0.73, 0.98 and 1.1, respectively, and r2 values for the linear correlations were 0.990, 0.983, 0.977 and 0.994, respectively. On the basis of data obtained after a single bolus injection in the rat, adequate predictions of propofol concentrations in critically ill patients can be made using allometric equations, despite the long-term nature of the use of the drug, the large number of infusion changes per day and/or differences in state of health and age.


CONCLUSIONS
For propofol, allometric scaling has proved to be valuable for cross species extrapolation. Furthermore, the use of the allometric equation between adults and children seems to be an adequate tool for the development of rational dosing schemes for children of varying body weights, and requires further study.
Knibbe
Catherijne A J
CA
Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, the Netherlands. knibhoef@worldonline.nl
Zuideveld
Klaas P
KP
Aarts
Leon P H J
LP
Kuks
Paul F M
PF
Danhof
Meindert
M
D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002675:Child, Preschool; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015742:Propofol / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D018686:Anesthetics, Intravenous; D015742:Propofol