Population Pharmacokinetic Analysis of Nonlinear Behavior of Piperacillin during Intermittent or Continuous Infusion in Patients with Cystic Fibrosis

Abstract

The purpose of this study was to describe the nonlinear pharmacokinetics of piperacillin observed during intermittent infusion and continuous infusion by using a nonparametric population modeling approach. Data were 120 serum piperacillin concentration measurements from eight adult cystic fibrosis (CF) patients. Individual pharmacokinetic parameter estimates during intermittent infusion or continuous infusion were calculated by noncompartmental analysis and with a maximum iterative two-stage Bayesian estimator. To simultaneously describe concentration-time data during intermittent infusion and continuous infusion, nonlinear models were parameterized as two-compartment Michaelis-Menten models. Models were fit to the data with the nonparametric expectation maximization algorithm. The calculations were executed on a remote supercomputer. Nonlinear models were evaluated by log-likelihood estimates, residual plots, and Piperacillin-tazobactam is a parenterally administered combination of a ␤-lactam antibiotic with a ␤-lactamase inhibitor (4). This drug combination is frequently used in the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF) because of its good bactericidal activity against Pseudomonas aeruginosa and gram-positive microorganisms (20). Piperacillin, like other ␤-lactam antibiotics, exhibits time-dependent killing, and the parameter for the bactericidal effect is the time during which the concentration of the drug exceeds the MIC (5). As shown for ceftazidime (23), continuous infusion of piperacillin-tazobactam may result in superior efficacy with equal or lower total daily doses. Administration by continuous infusion also has distinct advantages in CF home treatment programs (24). A recent report on continuous intravenous administration of vancomycin also emphasized this point (27).Data on the pharmacokinetics of piperacillin in patients with CF are scarce (12; J. S. Bertino, M. D. Reed, C. Meyers, and J. L. Blumer, Pediatr. Res. 16:1210A, abstr. 254, 1982), while data for the combination are lacking. Piperacillin-tazobactam is commonly administered by intermittent infusion. In non-CF patient populations and with this mode of administration, the pharmacokinetics of the ␤-lactamase inhibitor-antibiotic combination appeared to be linear (1), although nonlinear analysis was not addressed. Some authors, however, have argued for nonlinear behavior, and studies have documented evidence for decreasing clearance with increasing concentrations (2,3,19). Piperacillin is, for the most part, excreted through the kidneys by active tubular secretion and by glomerular filtration. A typical characteristic of the active secretion process is a limitation in the capacity of this process. This behavior can be described in terms of Michaelis-Menten (MM) kinetics, where the rate of active transport increases toward a maximum value (V max ) with increasing plasma drug concentrations (11). The concentration at which the rate is 50% of its maximum is the K m . At concentrations well below the K m , the r...

Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

“…While Vinks and colleagues published an MM model for this drug, there are several reasons for the dissimilar findings (35). First, their patient population was a specialized population (cystic fibrosis patients) that may have different K m and V max values for the anion-selective pumps in their renal tubules.…”

“…In the present study, the observed mean K m and V max values for the MM model were 307.03 Ϯ 147.4 and 812.75 Ϯ 801.64, respectively, which are substantially different from the observed mean K m and V max values (92.3 Ϯ 85.6 and 2,284 Ϯ 1,046) in the study of Vinks et al Second, the observed differences in the clearance models between studies may be secondary to the different infusion methods (intermittent versus continuous). In the study of Vinks et al, it was only with a continuous-infusion mode of administration that the benefits of the MM model were manifested (35). The nonlinear behavior of piperacillin in non-cystic fibrosis patients, therefore, may not become as evident with intermittent infusion as with continuous infusion, especially with continuous-infusion steadystate concentrations exceeding the K m .…”

“…To determine which PK model most accurately describes the elimination pathways for piperacillin, models were parameterized as two-compartment models with zero-order infusion and with elimination from the central compartment modeled as a MichaelisMenten (MM) process, as a MM process in parallel with first-order elimination, or as a first-order elimination process only. The models with zero-order input and MM with or without a parallel first-order elimination term were evaluated because of a recent study by Vinks et al (35). Population PK modeling for the MM model and a parallel first-order-MM model was performed with the BIG-NPAG program of Leary et al…”

Clinical Correlation of the CLSI Susceptibility Breakpoint for Piperacillin- Tazobactam against Extended-Spectrum-β-Lactamase-Producing Escherichia coli and Klebsiella Species

“…A one-compartment, first-order, intravenous model was used to calculate %TϾMIC. While there is disagreement as to the accuracy of a one-compartment model for pharmacodynamic analysis (30), the infusion time of piperacillin-tazobactam is relatively uniform, which negates much of the differences (13,29). Tazobactam exposure was estimated by calculating the area under the concentration-time curve (AUC 0-24 ).…”

Dose optimization of piperacillin/tazobactam in critically ill children

“…7 In addition, saturable renal elimination has been identified previously in adults. [8][9][10] To date, the pharmacokinetics of piperacillin/tazobactam have been described in (pre)term neonates and non-ICU children, but only in a small number of children admitted to the paediatric ICU (n=13 and n=12 patients), between 1 and 9 years of age. 7,[11][12][13][14][15] Any effort to define the dose rationale in infants and young children needs to account for the effect of developmental processes, which are known to affect drug exposure and potentially treatment response.…”