FDA shares research to improve dose selection in pediatric drug development

Regulatory NewsRegulatory News
| 23 November 2021 | By Mary Ellen Schneider 

Dose selection is a significant challenge in pediatric drug development; commonly used renal function equations can overestimate glomerular filtration rates and result in inaccurate predictions of drug elimination.
In a Regulatory Science in Action article, scientists from the US Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) shared findings about how adjustments to the estimated glomerular filtration rate (eGFR) equations could help improve the accuracy of predicted renal function in pediatric drug studies.
“Although the clearance of renally eliminated drugs might be overestimated when using creatinine-based renal function equations – especially for pediatric patients with low levels of serum creatinine – well-reasoned adjustments to methods of calculating eGFR values may improve the accuracy of predicted parameters,” CDER officials wrote. “Equations based on cystatin C levels or a combination of multiple renal biomarkers might be productive in this regard.”
When assessing renal function in pediatric patients, 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. These equations provide creatinine clearance as a proxy for the glomerular filtration rate. Calculations that rely on eGFR equations may use one or more renal function biomarkers or demographic parameters such as body weight.
After reviewing FDA-approved drug labels, CDER investigators noted that eGFR values can be used in a few different ways: as a continuous variable to directly calculate the dose; as a categorical variable to adjust the dose; and as an indication of whether the drug should be avoided in certain patients. They also found that the Schwartz equation was used most often when the eGFR equation was specified in the label.
To assess the accuracy of eGFR calculations, CDER scientists analyzed clinical pharmacokinetic data for four renally eliminated drugs: gadobutrol, gadoterate, amikacin, and vancomycin. In the case of gadobutrol, an imaging-contrast agent, the researchers compared the clinically observed clearance rate against the eGFR values calculated from a variety of equation versions. Five out of seven equation versions overpredicted the observed clearance rate for children less than 12 years old. The researchers also observed overestimation of drug clearance with the other three drugs.
The CDER scientists then attempted improve the eGFR predictive reliability by altering the coefficient (k) values in the Schwartz equation. To test this idea, they combined the data from the four renally eliminated drugs and created an integrated population pharmacokinetic model. “Values of eGFR recalculated with the combined (integrated population) model-derived k values, which were all lower than the coefficient (0.413) used for the bedside Schwartz equation, agreed more closely to observed drug clearance rates,” CDER officials wrote.
The research efforts have impacted pediatric drug regulatory review “by facilitating consensus on best practices for assessing pediatric renal function and dose selection in clinical trials and product labeling,” CDER officials wrote.
Regulatory Science in Action article  


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