Drug Dosing in Pediatric Acute Kidney Insufficiency and Renal Replacement Therapy

Drug dosing in the pediatric population can be a challenging task and is particularly problematic in patients with acute kidney insufficiency (AKI) or those receiving renal replacement therapy (RRT). Dosing studies with RRT are sparse, especially for methods such as continuous renal replacement therapy (CRRT) and newer hybrid forms of dialysis such as slow low-efficiency dialysis and extended daily dialysis. In fact, less than 20% of currently used medications have dosing recommendations for CRRT, and less than 1% have recommendations for new hybrid therapies. There are even fewer recommendations specific to pediatric patients. Therefore drug doses often are extrapolated from either the adult literature or clinical experience.

Several limitations exist with extrapolating drug doses for the pediatric population from the adult literature. First is the physiologic changes that occur during maturation that affect drug pharmacokinetics. For example, bioavailability is variable owing to changes in gastric acidity, motility, and enzymatic activity. Volume of distribution (V _d ), which is the mathematic concept representing the nonphysiologic compartment in which a drug disperses, is higher in children, particularly for drugs that are highly water soluble (e.g., aminoglycosides). Protein binding is reduced, thereby increasing the free fraction or pharmacologically active portion of the drug at the site of action. Drug metabolism (phase I and phase II reactions) and elimination pathways are immature at birth but generally reach adult levels within 1 year. Another limitation pertains to the methodology used in the adult literature. Many drug doses for CRRT are extrapolated from pharmacokinetic studies conducted in patients with chronic kidney disease on intermittent hemodialysis (IHD). They fail to account for the differences in nonrenal clearance that are observed in patients with AKI. Even studies that are specific to CRRT frequently use outdated CRRT technology and substandard dialysis doses, which can lead to dosing errors when applied to current practices. Furthermore, differences in drug removal may exist based on the method of clearance used because the efficiency of each mode can vary with each medication and its physical or chemical properties (i.e., molecular weight, water vs. lipid solubility). Finally, the dialysis prescription used in pediatric patients can provide greater clearance than that achievable with the same prescription used in adults. Because the dialysis prescription typically is measured by urea kinetic modeling (i.e., Kt/V where k = dialyzer clearance of urea, t = time of dialysis, and V = total body water) and V naturally is smaller in pediatric patients, greater clearance (and increased drug removal) can be obtained, in case K and t do not vary.

This chapter reviews principles of drug dosing in critically ill pediatric patients with AKI requiring RRT. The primary focus is to provide a framework for making dosing decisions rather than providing individual recommendations for specific agents given the lack of primary literature in this area and the variability that exists with local practices. Hopefully initiatives such as the Kidney Health Initiative, a partnership between the Food and Drug Administration and the American Society of Nephrology, will increase awareness for the importance of dosing studies in this realm.