Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia.

Abstract

Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two-compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 ± 12 years [means ± standard deviations] and weight of 77 ± 16 kg). Parameter estimates were CL of 18.0 ± 4.8 liters/h, volume of distribution of the central compartment of 14.3 ± 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 ± 1.35 h-1, and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 ± 7.81 h-1 High creatinine clearance (CLCR) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of >90% for an unbound concentration of piperacillin remaining above the MIC (fT>MIC) of 50%. Only continuous regimens achieved >90% PTA for 100% fT>MIC when CLCR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (<85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT>MIC FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CLCR or with known/presumed infections from high-MIC bacteria.

• Authors: Fekade Bruck Sime, Uwe Hahn, Morgyn S Warner, Ing Soo Tiong, Michael S Roberts, Jeffrey Lipman, Sandra L Peake, Jason A Roberts
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 61 Issue 11 (11 2017) ISSN: 1098-6596 [Electronic] United States
• PMID: 28807922 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 American Society for Microbiology.

Chemical References

• Anti-Bacterial Agents
• Piperacillin, Tazobactam Drug Combination
• Penicillanic Acid
• Creatinine
• Piperacillin

Topics

• Aged
• Anti-Bacterial Agents (pharmacokinetics, therapeutic use)
• Bacterial Infections (drug therapy)
• Creatinine (blood)
• Febrile Neutropenia (drug therapy)
• Female
• Humans
• Male
• Microbial Sensitivity Tests
• Middle Aged
• Monte Carlo Method
• Penicillanic Acid (analogs & derivatives, pharmacokinetics, therapeutic use)
• Piperacillin (pharmacokinetics, therapeutic use)
• Piperacillin, Tazobactam Drug Combination