Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia

Abstract

The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen-minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration-time curve over 24 h ≥ 96 µg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75-101) years, were investigated. The plasma-concentration-time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CL cr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CL cr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CL cr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 µg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CL cr of 50-60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

Population Pharmacokinetics and Dose Optimization of Piperacillin/tazobactam in Critically Ill Patients During Extracorporeal Membrane Oxygenation (ECMO) and Weaned from ECMO

“…Three piperacillin PK/PD targets are regularly used in the literature in critically ill patients:50% fT > MIC, 50% fT > 4 × MIC, and 100% fT > MIC [25,26]. When 50% ƒT > 4 × MIC of 16 mg/L was evaluated for piperacillin in consideration of conservative target, extended infusion of 4 g q6h could not achieve the desirable PTA in patients with CrCL > 20 mL/min; however, 50% fT > 16 mg/L re ects the worst-case associated with bacterial susceptibility in empirical treatment, and previous studies have shown these targets to be clinically meaningful [27].…”

An Algorithm for Nonparametric Estimation of a Multivariate Mixing Distribution with Applications to Population Pharmacokinetics

“…S-ADAPT is based on the ADAPT package developed by D’Argenio, Wang and Schumitzky. Ishihara et al [ 40 ] and Soraluce et al [ 41 ] use the industry standard parametric version of NONMEM. Allard et al [ 42 ] uses the stochastic approximation expectation maximization method (SAEM).…”

A Systematic Review on Antimicrobial Pharmacokinetic Differences between Asian and Non-Asian Adult Populations

“…Describing the PK of antimicrobials in the Asian population is important to determine dosing requirements for this population. Numerous countries in this region rely heavily on product information to guide antimicrobial dosing, which can potentially be flawed for critically ill patients [34][35][36]. Furthermore, dosing recommendations from the product information were mainly derived from dose-finding studies that mainly included subjects from non-Asian populations [37,38].…”