When Clinical Associate Professor Adam Frymoyer, MD, was a resident, he learned there was a lack of evidence to support most medication dosing strategies in babies. Neonates are historically an understudied patient population and most drugs don’t have formally FDA-approved labeling information for children.

This is problematic because infants undergo a period of profound maturation and stand to benefit if the right drugs are delivered in the correct doses at appropriate times. “How do you build a therapeutic program within academia to help shepherd the safe and efficacious use of medications in this group?” Dr. Frymoyer asks.

It’s a question he has focused his research career on answering. He is busy building a therapeutic framework at Stanford Children’s Health (SCH) and serves as a resource for other children’s hospitals looking to do the same.

Precision dosing at the bedside

In 2019, Dr. Frymoyer received an MCHRI Clinician Educator Award of $35,000 toward refining his model-informed precision dosing platform for vancomycin in children.

Vancomycin is a type of antibiotic that is used to target drug-resistant infections, specifically methicillin-resistant Staphylococcus aureus. To predict the sweet spot for vancomycin dosing, Dr. Frymoyer applies a population pharmacokinetic mathematical model he developed using data from prior patients who received vancomycin at Lucile Packard Children’s Hospital Stanford (LPCH) and combines this quantitative understanding with clinical information about a given infant like gestational age, weight, and serum creatinine level.

Despite the success of the model-informed precision dosing approach, making it readily accessible to providers during clinical care has been a challenge.  

To overcome this hurdle, Dr. Frymoyer partnered with San Francisco-based start-up InsightRX to create a clinical decision support tool that could be integrated within Stanford’s electronic medical record and automatically transmit relevant patient health data needed for the complex calculations. When a clinician is at the bedside, they can now receive individualized pharmacokinetic predictions and find the best dose for vancomycin with just one click. It’s point-of-care precision medicine. No complex math is required by the user.

According to Dr. Frymoyer, SCH is the first academic children’s hospital to report on the successful implementation and adoption of model-informed precision dosing that is fully integrated in the electronic medical record, allowing for dosing decisions to be made in real time. Research published in Frontiers in Pharmacology in April reports that 81 percent of users at Stanford Children’s agreed or strongly agreed that they were satisfied with the clinical decision support tool. What’s more, the platform has been designed so that it’s scalable for other medications.

Finding the best dose for the most critically ill infants

Morphine is another drug that’s commonly used in extremely ill term infants who suffer from hypoxic ischemic encephalopathy (HIE). Hypothermia has been proven to improve outcomes for infants with HIE, and morphine is administered for comfort and sedation while the baby is cooled.

Dr. Frymoyer received an MCHRI Pilot Early Career Award of $35,000 in 2014 to carry out a two-center prospective study to determine how morphine is metabolized in this specific group of babies. Based on the results, his team was able to create a customized dosing strategy for this unique population that is now used both at Stanford and the University of California, San Francisco—the participating center involved in the study. What’s more, it’s recommended by many experts in the field.  

Building on their existing knowledge of therapeutic dosing in neonates with HIE, Dr. Frymoyer recently applied for an R01 to explore if another drug, aminophylline, can be repurposed to help protect a baby’s kidneys after birth. Dr. Frymoyer and Associate Professor of Pediatrics Valerie Chock, MD, MS Epi, recently published a retrospective chart review in Pediatric Research that demonstrates a link between aminophylline and improved renal function. In a subsequent pharmacokinetic study, also appearing in Pediatric Research, they defined the aminophylline dose to advance in future clinical trials that would most likely be effective yet safe.

MCHRI fills gap in drug development for children, Frymoyer leads the charge

Given Dr. Frymoyer’s expertise in therapeutics, he currently serves as an integral part of MCHRI’s Drug & Device Development Service (or D³). He is the inaugural faculty advisor for the D³ Training Program, designed as a unique educational ‘hands-on’ internship where trainees and junior faculty engage with industy to better understand the medical product development process. Participation in D³ further strengthens Dr. Frymoyer’s work; for instance, it will provide investigational new drug (IND) support and maintenance over the life of his aminophylline R01 application.

“When I first came to Stanford and was a young investigator to now becoming a more mid-level investigator, MCHRI funding opportunities and initiatives have allowed me to explore areas of research maybe that are a little more risky or areas that maybe I wouldn't have the opportunity to explore otherwise,” he says. “They allowed me to develop an independent research framework that hopefully then leads to bigger research funding that answers impactful questions.”

This story is a complimentary piece to a larger article. To read the article, click here.

BY LAURA HEDLI

Laura Hedli is a writer for the Division of Neonatal and Developmental Medicine in the Department of Pediatrics and contributes stories to the Stanford Maternal and Child Health Research Institute.