Population Pharmacokinetics of Piperacillin Using Scavenged Samples From Preterm Infants

Objectives: Piperacillin is often used in preterm infants for intraabdominal infections; however, dosing has been derived from small single-center studies excluding extremely preterm infants at a highest risk for these infections. We evaluated the population pharmacokinetics (PK) of piperacillin using targeted sparse sampling and scavenged samples obtained from preterm infants <= 32 weeks of gestational age at birth and <120 postnatal days. Materials and Methods: A 5-center study was performed. A population PK model using nonlinear mixed effect modeling was developed. Covariate effects were evaluated based on the estimated precision and clinical significance. Results: Fifty-six preterm infants were evaluated and had a median (range) gestational age at birth of 25 (22-32) weeks, a postnatal age of 17 (1-77) days, a postmenstrual age of 29 (23-40) weeks, and a weight of 867 (400-2580) g. The final PK data set contained 211 samples; 202/211 (96%) were scavenged from the discarded clinical specimens. Piperacillin population PK was best described by a 1-compartment model. The population mean clearance (CL) was derived by the equation CL (L/h) = 0.479 x (weight)(0.75) x 0.5/serum creatinine and using a volume of distribution (V) (L) of 2.91 x (weight). The relative standard errors around parameter estimates ranged from 13.7% to 32.2%. A trend toward increased CL was observed with increasing gestational age at birth; infants with serum creatinine >= 1.2 mg/dL had a 60% reduction in piperacillin CL. The majority (>70%) of infants did not meet predefined pharmacodynamic efficacy targets. Conclusions: Scavenged PK sampling is a minimal-risk approach that can provide meaningful information related to the development of PK models but not dosing recommendations for piperacillin. The utility of scavenged sampling in providing definitive dosing recommendations may be drug dependent and needs to be further explored.