Predicting the Pharmacokinetics of Piperacillin and Tazobactam in Preterm and Term Neonates Using Physiologically Based Pharmacokinetic Modeling

Abstract A probabilistic-based seven-compartment fit for purpose 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. Anthropomorphic maturation equations with distributions were used to account for variability in growth patterns for neonates born premature (gestation age ≥ 25 weeks). Renal excretion, the primary pathway for elimination of these drugs from the body, was described by passive diffusion (glomerular filtration, GFR) and 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. After accounting for variability in maturation of growth (organs, kidney function and blood flows) model predictions did not account for all the observed variability in the pharmacokinetic plasma data for PIP and TAZ. For the 31 preterm and term neonates, the PBPK model for PIP and TAZ, with no adjustments in model parameters, was judged successful for 48% and 43% of the preterm neonates and 25% of the term neonates. Further refinements in model parameters to increase model performance include experiments to determine plasma protein binding in preterm and term neonates and solubility or partitioning of PIP and TAZ into tissues. A better understanding of the role of illness on modifying pharmacokinetic behavior of PIP and TAZ is needed.