Pharmacokinetic Variability in Pediatrics and Intensive Care: Toward a Personalized Dosing Approach

Abstract

 Providing a safe and efficacious drug therapy for large and often heterogeneous populations is 
a challenging objective in clinical drug development and routine clinical practice. It has been known for years 
that the optimum dose required for many therapeutic agents among individuals is quite variable. A wide 
interindividual pharmacokinetic variability was described in clinically relevant populations such as pediatrics 
and critically ill patients. The aim of this article was to present the main individual factors influencing 
variability in these two populations and their applications. Growth and development are two specific features 
of children that are not observed in adults. And critically ill patients have a much higher level of sickness 
severity that is associated with profound pathophysiological changes. These particular features could lead to 
difficulties to attain therapeutic targets. Nonlinear mixed effects modeling is a common approach to identify 
unexplained population variability. This approach is often applied to evaluate and optimize drug therapy in 
particular populations. Numerous studies have been conducted in these two specific populations to 
characterize pharmacokinetic parameters and to identify individual factors influencing variability. Size, age 
and organ function appeared to be the main factors influencing pharmacokinetics in pediatrics. Factors 
influencing pharmacokinetics in critically ill patients were mainly cardiovascular system, organ dysfunction 
and organ support. Dosage individualization seems to be a key issue to optimize drug treatment in these 
specific populations. Clinically utility and safety of a model-based personalized drug therapy has been 
demonstrated for vancomycin in pediatrics. Many programs were available to optimize drug regimens, 
especially for antibiotic drugs in critically ill patients. This innovative personalized dosing approach is a 
promising way to optimize drug therapy in clinically relevant populations, such as pediatrics and critically ill 
patients