Population pharmacokinetics differ from conventional pharmacokinetic approaches by allowing true interpatient pharmacokinetic variability to be modeled. The behavior of a drug within a population can be summarized using measures of central tendency and dispersions for each model parameter (11
). Using simulation techniques, this information can be used to provide predictions as to the likely behavior of a drug when administered to a large number of patients.
Population modeling of pediatric patients presents a number of challenges. Most important is the effect of size on drug disposition and elimination. The sizes of pediatric patients vary by more than an order of magnitude. To enable a more complete understanding of the importance of weight as a covariate, we modeled absolute (rather than weight-adjusted) dosages, volumes, and clearances. The improved log-likelihood values of the two models in which weight was incorporated as a covariate suggested that it accounted for a portion of the residual interpatient variability observed using the standard model (Table ).
Allometry is the field of study which relates bodily function and morphology to body size (7
). An understanding of allometric relationships is important, as adult pharmacokinetic models cannot necessarily be used to predict appropriate dosing regimens for children. An abundance of data suggests that organisms do not exhibit simple geometric scaling; this is a consequence of powerful biological constraints on structure and function that do not allow organisms to maintain the same geometric relationships as size changes (7
). The 3/4 power law has been extensively used to model the relationship between physiological functions, such as metabolic rate and clearance, and size (14
). Body surface area represents a measure of size and has been used to guide pediatric dosing. Body surface area can be related to weight by using a 2/3 power scaling exponent (14
). Predictions of clearance based upon body surface area and the 3/4 power model are similar and certainly superior to assuming that clearance is directly proportional to weight (14
). In the current study, the decision to use a 3/4 power model, rather than a surface area model, was based upon two observations: first, many body functions scale predictably with an allometric 3/4 power model rather than with body surface area (7
); second, the slope of the regression line in Fig. better approximated 3/4 rather than 2/3. Furthermore, there is a theoretical basis for the allometric 3/4 power law which provides for a deeper understanding for the observation that clearance is proportionally higher in smaller children. There appear to be inherent limitations in the efficiency with which a progressively larger mass of tissue (in this case the liver) can be supplied with nutrients (or in the case of drug clearance, with the drug itself). Consequently, the rate of clearance in larger organisms is slower than predicted on the basis of tissue mass alone (conversely, the rate of clearance in smaller children is higher than predicted from data derived in adults). These concepts are presented in detail elsewhere (7
). The nonlinear relationship between weight and clearance (resulting from inherent physiological constraints) means that as weight decreases, progressively higher dosages of micafungin (on a mg/kg basis) are required to achieve equivalent drug exposure; these increased dosages are higher than predicted on the basis of weight alone and are especially so in children weighing <10 to 15 kg.
A reasonable aim of pediatric dosing is to ensure levels of drug exposure which are comparable to those achievable in adults and which approximate those for which antifungal efficacy has been established. The current study demonstrates that smaller children require higher dosages of micafungin to ensure mean levels of drug exposure equivalent to those observed in larger children and adults. This can be achieved by increasing the dosage of micafungin at some (arbitrarily chosen) cutoff weight. In the current study, however, we were able to describe the continuous relationship between dose and weight and use this to precisely define antifungal dosing in pediatric patients. The Monte Carlo simulations also demonstrated that there is a degree of interpatient variability in serum drug concentrations and exposures following the administration of micafungin (Fig. ); this observation may prompt an increase in dosage in the circumstance of a suboptimal therapeutic response despite the administration of a seemingly appropriate dose of micafungin.
In summary, the population pharmacokinetics of micafungin in children aged 2 to 17 years demonstrate the importance of considering and incorporating weight as a covariate in order to adequately describe drug behavior. The allometric power model developed in this study enables the identification of pediatric dosage regimens of micafungin that, based upon Monte Carlo simulations, result in drug exposure that is equivalent to that observed in adults, for whom antifungal efficacy has been established.