CDER scientists are investigating how to improve pediatric dose selection by predicting drug clearance from renal function equations.
Challenges in Pediatric Dose Selection
How to select the right dose for pediatric patients is a fundamental challenge in pediatric drug development. In children, rapid changes in body size and organ function bring large inter- and intraindividual variabilities in the time course that drugs move through the body to elicit their pharmacodynamic effects. FDA is frequently consulted by sponsors about the acceptability of using renal function equations to predict exposures for renally eliminated drugs in the pediatric patient population; however, such predictions warrant careful evaluation. As revealed by the data in new drug applications, the commonly used renal function equations for children can markedly overestimate glomerular filtration rates and result in unrealistic predictions regarding pediatric dosing.
Renal Function Equations in Pediatric Dose Selection
For drugs eliminated mainly via the kidney, estimation of renal function will be used to determine the dose. Various equations have been developed to determine renal function and to interpret drug elimination profiles in pediatric patients. In drug development, an estimator of renal maturation can be incorporated into pharmacokinetic models to predict drug clearance and inform appropriate dose selection in pediatric patients. In clinical settings, individual dose adjustment can be guided through the use of estimated glomerular filtration rate (eGFR) equations as descriptors of renal function. The most commonly used eGFR equations are the “bedside” version of the Schwartz equation for children less than 12 years of age, and the Cockcroft-Gault equation for patients 12 years of age and older, providing creatinine clearance as a proxy for glomerular filtration rate. (See the FDA draft guidance for industry Pediatric Clinical Pharmacology Studies). Calculations based on eGFR equations may use one or more renal function biomarkers; demographic parameters such as body weight, height, age, and sex may also be incorporated.
To get an overview of the eGFR equations currently recommended in product labeling for pediatric patients, CDER investigators searched through FDA-approved drug labels and found that a given eGFR value can be used in multiple ways: 1) as a continuous variable to directly calculate the dose; 2) as a categorical variable to adjust the dose; or 3) as an indication of whether the drug should be avoided for a subgroup of pediatric patients. Among those drugs where an eGFR equation was specified in the label, a version of the Schwartz equation was given most often (Figure 1).
Renal Function Equations and Drug Clearance Predictability
To evaluate the potential of renal function equations to guide pediatric dose selection, CDER researchers sought to identify the major factors affecting the predictive accuracy of the Schwartz equation. For those drugs that are predominantly eliminated via the kidney, elimination from the circulatory system is expected to approximate renal clearance, thereby offering an opportunity to assess the accuracy of eGFR calculations. Following this logic, researchers analyzed clinical pharmacokinetic data of four renally eliminated drugs in pediatric patients and compared their observed values against eGFR calculations. For example, for gadobutrol, an intravenously administered imaging-contrast agent, 99% of elimination from the body occurs via glomerular filtration, thereby allowing one to determine its rate of clearance directly from clinically observed pharmacokinetic data. Figure 2 compared the clinically observed value against eGFR values calculated from a variety of equation versions. For children less than 12 years old, five out of seven equation versions, including the original and bedside Schwartz equations, in fact overpredicted the observed clearance rate for gadobutrol.
In addition to gadobutrol, analyses of three other drugs were performed using the bedside Schwartz equation. The three additional drugs—namely, gadoterate, amikacin, and vancomyci...
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