Dear Editor, In response to our original publication, Dr. Mahmood proposes the use of an allometric scaling with an exponent of 1.2 on body weight to be used for predictions in children< 3 months. Dr. Mahmood considers the use of a single or variable exponent to be advantageous in relation to allometric scaling with a fixed exponent of 0.75 in association with a maturation function. According to Dr. Mahmood, exponents of allometry have no biological or physiological meaning and are dependent on the data. In this respect, a maturation function merely serves as a correction factor to reduce the prediction error introduced by the use of a fixed exponent. The authors share Dr. Mahmood’s concerns in relation to the use of a fixed exponent of 0.75 in association with a maturation function. Our group has previously shown that this maturation function is not system but compound specific, which could indicate that this function is at least partially a correction factor to compensate for the error introduced by fixing the exponent. Our original publication confirms these previous findings by showing that this methodology lacks predictive power when applied in association with a maturation function representing enzyme activity. Finally, we also believe that the allometry exponent is dependent on the data and therefore a data-driven approach in which the exponent estimated is the best way forward for defining dose guidelines not only in children but also in all special populations. However, the fact that the exponent is dependent on the data hampers its use as a universal constant value for predictions of all compounds disregarding their specific properties. Hence, in cases in which no prior data are available in the target population, a more mechanistic approach should be considered. The advantage of a mechanistic approach is that it makes a clear distinction between system and compoundspecific parameters, thereby allowing discrete changes in the physiology to be considered simultaneously. This important feature also allows its application for predictions of clearance not only in children but also in other special populations, such as the hepatically and renally impaired and the elderly patients. The accuracy of mechanistic approaches was demonstrated not only for prediction of clearance in children but also when used in combinationwith a population approach for the prediction of full pharmacokinetic profiles in hepatically and renally impaired patients.
A. Strougo, A. Yassen, M. Danhof
The Journal of Clinical Pharmacology