Prediction of propofol clearance in children from an allometric model developed in rats, children and adults versus a 0.75 fixed-exponent allometric model

Abstract

For propofol clearance, allometric scaling has been applied successfully for extrapolations between species (rats and humans) and within the human bodyweight range (children and adults). In this analysis, the human bodyweight range is explored to determine for which range an allometric model with a fixed or estimated exponent can be used to predict propofol clearance, without correction for maturation. The predictive value of the allometric equation, clearance (CL) is equal to 0.071 x bodyweight in kg0.78, which was developed from rats, children and adults, and the predictive value of a fixed exponent allometric model derived from the basal metabolic rate, CL is equal to CL standardized to a 70 kg adult x (bodyweight in kg standardized to a 70 kg adult)0.75, were evaluated across five independent patient groups including (i) 25 (pre)term neonates with a postmenstrual age of 27-43 weeks; (ii) 22 postoperative infants aged 4-18 months; (iii) 12 toddlers aged 1-3 years; (iv) 14 adolescents aged 10-20 years; and (v) 26 critically ill adults sedated long term. The median percentage error of the predictions was calculated using the equation %error = (CL(allometric) - CL(i))/CL(i) x 100, where CL(allometric) is the predicted propofol clearance from the allometric equations for each individual and CL(i) is the individual-predicted (post hoc) propofol clearance value derived from published population pharmacokinetic models. In neonates, the allometric model developed from rats, children and adults, and the fixed-exponent allometric model, systematically overpredicted individual propofol clearance, with median percentage errors of 288% and 216%, respectively, whereas in infants, both models systematically underpredicted individual propofol clearance, with median percentage errors of -43% and -55%, respectively. In toddlers, adolescents and adults, both models performed reasonably well, with median percentage errors of -12% and -32%, respectively, in toddlers, 16% and -14%, respectively, in adolescents, and 12% and -18%, respectively, in adults. Both allometric models based on bodyweight alone may be of use to predict propofol clearance in individuals older than 2 years. Approaches that also incorporate maturation are required to predict clearance under the age of 2 years.