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 twocompartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 Ϯ 12 years [means Ϯ standard deviations] and weight of 77 Ϯ 16 kg). Parameter estimates were CL of 18.0 Ϯ 4.8 liters/h, volume of distribution of the central compartment of 14.3 Ϯ 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 Ϯ 1.35 h Ϫ1 , and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 Ϯ 7.81 h Ϫ1 . High creatinine clearance (CL CR ) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of Ͼ90% for an unbound concentration of piperacillin remaining above the MIC (fT ϾMIC ) of 50%. Only continuous regimens achieved Ͼ90% PTA for 100% fT ϾMIC when CL CR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (Ͻ85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT ϾMIC . 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 CL CR or with known/presumed infections from high-MIC bacteria.KEYWORDS febrile neutropenia, piperacillin, population pharmacokinetics

Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?

“…Furthermore, higher doses would result in very high peak concentrations, which have been associated with increased prevalence of adverse events such as neurotoxicity . Even though β‐lactams have a wide safety margin and are generally well tolerated, a clear cutoff concentration that defines the risk of neurotoxicity remains unknown . Consequently, alternative dosing strategies are required to increase f T > MIC and ensure sufficient PTA achievement.…”

“…10 Even thoughlactams have a wide safety margin and are generally well tolerated, a clear cutoff concentration that defines the risk of neurotoxicity remains unknown. 30 Consequently, alternative dosing strategies are required to increase fT > MIC and ensure sufficient PTA achievement. Because EI only covered MIC 90 when assessing 50% fT > 4× MIC and did not target higher MICs, CI should be strongly considered as first-choice empiric therapy in this population ( Table 2).…”

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

“…The PK models of PIPC and TAZ have been previously described by both one- [16,18,19] and two-compartment models [10,[12][13][14][15]17]. In our study, plasma-concentration-time data were analyzed by a two-compartment model because the AIC values of the two-compartment model (1040.069, PIPC and 596.955, TAZ) were lower than those of the one-compartment model (1063.038, PIPC and 615.059, TAZ).…”

“…Some population PK studies concerning PIPC/TAZ in adult subjects have been reported [10][11][12][13][14][15][16][17][18][19]. In many antibiotics, including carbapenems and cephems, elderly patients have been reported to have different PK parameters than younger patients [21][22][23].…”

“…Establishing a population PK model is necessary in planning an optimized therapeutic regimen. Population PK models on PIPC/TAZ have been reported in young adult patients with nosocomial infections [10,11], sepsis [12,13], febrile neutropenia [14], acute infections [15], and obesity [16], and those undergoing continuous renal replacement therapy [17]. Additionally, antimicrobial chemotherapy with a combination of a β-lactam/β-lactamase inhibitor requires that there is a sufficient amount of the inhibitor to inactivate β-lactamases, which allows the β-lactam to exhibit its antibacterial activity [18].…”