Finding the right dosing for children

Prescribe at your own risk. That is the general feeling that most doctors get when prescribing medicine to children. Due to ethical and legal challenges, conducting clinical trials on children has proven to be a major obstacle for drug researchers. In fact, many prescription drugs rarely go through clinical trials using children. As a result, doctors only have two options in pediatric care: 1. Don’t prescribe children drugs shown to be effective in adults, or 2. Prescribe drugs off-label to children at their own risk. That’s where Dr. Bhagwat Prasad, Associate Professor in Pharmaceutical Sciences at WSU, is transforming pediatric precision medicine so that drugs can safely be prescribed to children.

Bhagwat Prasad,Associate Professor in Pharmaceutical Sciences at WSU, and his research team.

“Only 28 of 399 drugs prescribed to younger children between 1997 and 2010 have been studied for child safety and efficacy levels. Having some point of reference as to how to dose children is critical in understanding the long-term impact on the essential organs such as brain, kidneys and liver,” said Prasad, who recently joined WSU after more than eight years at the University of Washington’s Department of Pharmaceutics.

Having some point of reference as to how to dose children is critical in understanding the long-term impact on the essential organs such as brain, kidneys and liver.

Children remain one of the most understudied population. The difference in physiology between children and adults is significant, not to mention the variability between genes, sex, and weight, among many other factors including potential drug interactions, which can cause a range of unpredictable outcomes in drug metabolism. For example, UGT2B17, a gene coding responsible for the elimination of potentially toxic xenobiotics and endogenous compounds, is not expressed in pre-pubescent children under the age of nine. If a child were given a drug requiring UGT2B17 enzyme to metabolize the drug, then toxicity would be a very likely outcome.

Prasad’s research aims to bridge the existing gap in the data with a refined and mechanistic understanding of the developmental changes (ontogeny) in drug metabolizing enzymes and transporters in adults versus children population using quantitative mass spectrometry. The quantified proteomics and metabolomics data derived using pediatric tissues and biofluids when combined with drug-dependent parameters is crucial to develop pediatric physiologically-based pharmacokinetic (pPBPK) models. These models help researchers to better understand the lifecycle and metabolism of a drug and give a more accurate dosing recommendation when considering pediatric dosing—particularly in clinical trials.

“If we can better understand all the variables in drug metabolism and possible interactions, it takes the burden off of doctors having to prescribe a dosage to a child based on what little evidence there is on pediatric dosing,” said Prasad.

In the long-term, Prasad’s lab is focused on building refined p-PBPK models integrated with children’s developmental and physiological factors to better predicting safe pediatric dosage levels.  “For parents, children are their most valuable assets. By researching and understanding in greater detail the physiology, and mechanisms behind drug metabolism in children, we are safeguarding what is most important to us,” said Prasad.