September 21, 2021
by Jeff Fisher
Edited by Donald Mattison Lee-Ann Halbert
I was the senior author of one chapter in the newly released textbook, “Clinical Pharmacology During Pregnancy, second edition.” Coauthors on the original research publications include scientists from the US FDA, Duke University, and Proctor & Gamble Corporation. The editors were Dr Donald Mattison and Ms. Lee-Ann Halbert. Dr Mattison, a physician/researcher has been a strong advocate of computational methods in the field of toxicology throughout his distinguished career with a focus on reproduction and development. Ms. Halbert, an attorney, is now a practicing nurse.
The title of the chapter is, “Challenges in Predicting the Pharmacokinetics of Drugs in Premature and Mature Newborns: Example with Piperacillin and Tazobactam”. Physiological based pharmacokinetic (PBPK) models for drugs administered to newborns and infants can assist with drug dose selection. Our goal was to better understand how premature birth influences the pharmacokinetics of drugs given to these newborns soon after birth and if the observed variability in measured drug concentrations in newborn plasma can be explained by maturation variability. For the newborn PBPK model we created time varying maturation equations for several physiological and biochemical parameters, including data-derived estimates for the variability of each parameter, when available. For this case study we used individual pharmacokinetic data collected in hospitalized newborns and infants treated for infections intravenously with the combination drug piperacillin and tazobactam. Our modeling and simulation findings suggest that maturation and growth of the preterm newborn, especially near 25 weeks gestation, is different than for a full-term newborn for many months after birth. Most predictions were acceptable and largely within the 5th and 95th percentile predictions based on Monte Carlo methods. Some plasma concentrations were outside the 5th and 95th percentile predictions. Our conclusions were that model parameter variability may be greater than previously assumed (due to a lack of knowledge) and organ impairment for some neonates may both contribute to lack of agreement between observation and computed prediction.
The ongoing computational efforts for drugs in the pediatrics will help advance computational methods for the very young for the toxicology community. Drugs and environmental compounds can affect individuals differently depending on age: ScitoVation’s expertise in pharmacokinetic modeling can help answer these types of challenges in drug and chemical distribution.