Perinatal Health Center of Excellence: Development and Validation of Predictive Systems

Activity: FDA Grand Rounds
Amy Inselman, PhD Faculty
Staff Fellow
National Center for Toxicological Research
Jeffrey Fisher, PhD Faculty
Research Toxicologist
Devin Thomas, LCDR, MPH, CHES Activity Coordinator
Health Promotions Specialist
Thu, 2/14 2019: 12:00 PM  - 1:00 PM 
Regularly Scheduled Series 
WO 32: 1211 
The Perinatal Health Center of Excellence (PHCE) was established to promote collaboration across FDA Centers and Offices to support research that applies to the understudied perinatal population which includes neonates, infants and pregnant mothers. One of the priority areas identified by the PHCE is the development of novel modeling and simulation approaches to evaluate the safety, efficacy and potential toxicity of FDA-regulated products. An example of a recently developed PBPK model for preterm and term neonates will be highlighted.
A probabilistic-based 7 compartment PBPK model for the preterm and term neonates was constructed and used with the combination antimicrobial drugs piperacillin (PIP) and tazobactam (TAZ) as a case study. The PBPK model is based on published pharmacokinetic kinetic data sets in 31 preterm and term neonates. Anthropomorphic equations for maturation (with distributions patterns) were derived from published data. Renal excretion, the primary pathway for elimination of these drugs from the body, was described by passive diffusion (GFR) and/or active tubular secretion. Tubular secretion rates were calculated using in-vitro to in-vivo extrapolation methods for OAT1 and OAT3 protein transporters. Competitive inhibition of each anion (PIP and TAZ) for tubular secretion by the OAT transporters suggested that PIP decreased the systemic clearance rate of TAZ.


Describe the goals and priority areas of the PHCE.|List of key physiology parameters for development of a preterm and neonate PBPK model.|List challenges in collecting plasma samples and predicting drug plasma concentrations in neonates using a PBPK model.|Explain (qualitatively) likely sources responsible for the observed variability in measured plasma drug concentrations.