Population pharmacokinetic analysis and dosing optimization of polymyxin B in critically ill patients

Abstract

Objectives: Since the global broadcast of multidrug-resistant gram-negative bacteria is accelerating, the use of Polymyxin B is sharply increasing, especially in critically ill patients. Unsatisfactory therapeutic effects were obtained because of the abnormal physiological function in critically ill patients. Therefore, the determination of optimal polymyxin B dosage becomes highly urgent. This study aimed to illustrate the polymyxin B pharmacokinetic characteristics by defining the influencing factors and optimizing the dosing regimens to achieve clinical effectiveness. Methods: Steady-state concentrations of polymyxin B from twenty-two critically ill patients were detected by a verified liquid chromatography-tandem mass spectrometry approach. The information on age, weight, serum creatinine, albumin levels, and Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score was also collected. The population PK parameters were calculated by the non-parametric adaptive grid method in Pmetrics software, and the pharmacokinetic/pharmacodynamics target attainment rate was determined by the Monte Carlo simulation method. Results: The central clearance and apparent volume of distribution for polymyxin B were lower in critically ill patients (1.24 ± 0.38 L h^-1 and 16.64 ± 12.74 L, respectively). Moreover, albumin (ALB) levels can be used to explain the variability in clearance, and age can be used to describe the variability in the apparent volume of distribution. For maintaining clinical effectiveness and lowering toxicity, 75 mg q12 h is the recommended dosing regimen for most patients suffering from severe infections. Conclusion: This study has clearly defined that in critically ill patients, age and ALB levels are potentially important factors for the PK parameters of polymyxin B. Since older critically ill patients tend to have lower ALB levels, so higher dosages of polymyxin B are necessary for efficacy.

Keywords: albumin levels; critically ill patients; dosing optimization; polymyxin B; population pharmacokinetics.

FIGURE 1

Covariates relationship using a two-compartment base model of individual polymyxin B apparent clearance estimates versus ALB (A), the volume of distribution versus age (B), the volume of distribution versus APACHE-II scores (C). Shadow area, 95% confidence interval.

FIGURE 2

Observed concentrations versus Population Predicted (A) and Individual Posterior Predicted (B). Weighted residuals plotted against predicted concentrations (C); Weighted residuals plotted against time post-administration (D).

FIGURE 3

Probability of target attainment (PTA) of AUC/MIC ≥ 50 for the simulated polymyxin B dosing regimens in patients according to different ALB and age ^a. (A) ALB = 23.1–24.9 g L^-1, age = 34 years; (B) ALB = 23.1–24.9 g L^-1, age = 68 years; (C) ALB = 23.1–24.9 g L^-1, age = 93 years; (D) ALB = 25–34.9 g L^-1, age = 34 years; (E) ALB = 25–34.9 g L^-1, age = 68 years; (F) ALB = 25–34.9 g L^-1, age = 93 years; (G) ALB = 35–41.5 g L^-1, age = 34 years; (H) ALB = 35–41.5 g L^-1, age = 68 years; (I) ALB = 35–41.5 g L^-1, age = 93 years.^a The age were the 5th percentile, median, and 95th percentile values of the age of patients.

FIGURE 4

Probability of target attainment (PTA) for toxicity is defined as an AUC_ss,24h >100 mg∙h∙L^-1 for polymyxin B dosing regimens administered to patients. (A) age = 34 years; (B) age = 68 years; (C) age = 93 years ^a. (Ⅰ): 100 mg q12 h; (Ⅱ): 75 mg q12 h; (Ⅲ): 60 mg q12 h; (Ⅳ):50 mg q12 h; (Ⅴ):40 mg q12 h. ^a The age were the patients’ 5th, median, and 95th values. AUC _{ss, 24h}, an area under the plasma–concentration-time curve across 24 h at steady state.