Population Pharmacokinetics of Piperacillin Using Scavenged Samples From Preterm Infants

Abstract

Objectives Piperacillin is often used in preterm infants for intra-abdominal infections; however, dosing has been derived from small single-center studies excluding extremely preterm infants at 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 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 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) grams. The final PK data set contained 211 samples; 202/211 (96%) were scavenged from 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 (liter/h)=0.479 x (weight)0.75 x 0.5/serum creatinine and using a volume of distribution (V) (liter) of 2.91 x (weight). The relative standard errors around parameter estimates ranged from 13.7–32.2%. A trend towards 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 pre-defined pharmacodynamic efficacy targets. Conclusions Scavenged PK sampling is a minimal-risk approach that can provide meaningful information related to 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.

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

“…The scavenged samples were as informative as the scheduled samples and did not bias parameter estimates. Scavenged PK sampling is particularly effective in populations that are difficult to study, such as infants, and has been successfully used in population PK studies of anti-infection drugs (16,17). In addition, scavenged sampling is useful for drugs with long half-lives where traditional sampling schemes may not capture the full PK profile.…”

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

“…Previous studies have utilized one-and two-compartment models to describe piperacillin and/or tazobactam serum concentrationtime data in pediatric patients receiving TZP by the traditional 0.5-h infusion (14,15,24,27,28,40). However, the rate constants for the transfer of piperacillin between the central and peripheral compartments are rapid in young children and distribution may be complete (or nearly complete) by the end of the 4-h infusion, which results in a better fit with a one-compartment model (14).…”

“…Pharmacodynamic predictors of efficacy (e.g., T MIC ) for antibiotics do not change from the adult to the child. While evaluations of TZP pharmacokinetics in children are available, there are currently no published pharmacokinetic and pharmacodynamic data from children receiving extended-infusion TZP to guide optimal dosing on the basis of attainment of the target T MIC (14,15,(20)(21)(22)(23)(24)(25)(26)(27)(28). In addition, data regarding the population pharmacokinetics of tazobactam in children are limited (27,28).…”

Paediatric pharmacokinetics: key considerations

“…Combining drug analysis with routine clinical blood sampling can be useful in paediatric studies although it is essential that the timings of sampling relative to the dose administration are recorded accurately. These scavenged samples have been used successfully in studies in pre-term infants [83,84].…”