Population Pharmacokinetics of Intravenous Polymyxin B from Clinical Samples

Study design.A retrospective study of adult patients (≥18 years of age) admitted to New York-Presbyterian Hospital between January 2009 and December 2015 who underwent therapeutic drug monitoring of intravenous polymyxin B was conducted. The study was approved by the Columbia University Irving Medical Center Institutional Review Board with a waiver for informed consent and by Midwestern University for deidentified data analysis.

Inclusion required receipt of polymyxin B for treatment of a suspected or documented Gram-negative bacterial infection. Polymyxin B treatment, dose, and duration of use were ultimately at the discretion of the primary medical team; however, institutional dosing guidelines were provided to practitioners. Prior to 2014, institutional guidelines for polymyxin B dosing recommended dose adjustment for renal dysfunction, specifically, for an estimated creatinine clearance of less than 80 ml/min. Starting in 2014, dosing guidelines no longer recommended dose adjustments for renal dysfunction (1.5 mg/kg/dose every 12 h). Across all study years, loading doses of 2.5 to 3 mg/kg of total body weight were recommended for dosing of polymyxin B, with no specific maximum dose being recommended. The standard infusion time was 1 h but could be lengthened as needed to increase patient tolerability.

The following demographic and clinical data were collected from the electronic medical record: basic demographics; the type of infection; the bacterial organism targeted; the serum creatinine concentration prior to and during polymyxin B therapy; details of intravenous polymyxin B therapy, including the timing and concentration of every dose; the clinical resolution of infection; and any toxicity, including acute kidney injury or neurotoxicity. Only patients with at least two plasma polymyxin B assays were included. Cystic fibrosis patients and those receiving renal replacement therapy or treatment via some other extracorporeal device (e.g., extracorporeal membrane oxygenation) at the start of polymyxin B treatment or at the time of sampling were excluded from the analysis.

Blood samples for polymyxin B therapeutic drug monitoring were obtained on or after day 3 of therapy and prepared as plasma (15). Troughs were typically obtained within 60 min of a dose, and peaks were typically obtained 15 to 60 min after the end of the infusion. All samples included in the analysis for an individual patient were collected during the same dosing interval. Exact polymyxin B dosing times and blood collection times were documented for each patient. Polymyxin B concentrations were analyzed using a validated high-performance liquid chromatography-mass spectrometry method, as previously described (15). In brief, the lower limit of quantitation was 100 ng/ml.

Population pharmacokinetic modeling.A population pharmacokinetic model was developed and fit to the polymyxin B concentration-time data using a nonlinear mixed-effects modeling approach with Monolix 2016R1 software (Lixoft, Orsay, France). Model parameters were estimated using the stochastic approximation expectation-maximization algorithm with a Markov chain Monte Carlo procedure to compute the maximum likelihood estimates for the final population pharmacokinetic parameters (16, 17). All parameters were assumed to be log normally distributed. One- and two-compartment models were tested on the basis of previous pharmacokinetic studies (7, 10, 18, 19). The log-likelihood ratio test was utilized to compare competing models. A P value of <0.05 was required for increased complexity with agreement from the Akaike information criterion (AIC). The two-compartment model was fit to the polymyxin B data, parameterized as CL (in liters per hour), V (in liters), the volume of distribution of the peripheral compartment (in liters), and intercompartmental clearance (in liters per hour).

Because polymyxin B is conventionally dosed on the basis of weight, the effect of total body weight on clearance was evaluated as follows: log(CL_i) = log(CL_pop) + beta · log[TBW(i)/70], where CL_i and CL_pop are the clearance of the individual and the population, respectively, and TBW(i) is the total body weight of the individual.

Retention of total body weight (TBW) as a covariate required an improved AIC. Constant and combined error models were explored to describe the residual unexplained variability of the finalized model. The final model was selected on the basis of minimization of AIC, visual assessment of goodness-of-fit plots (including quantile-quantile plots), the distribution of the population and individual weighted residuals, and the intersubject variability for the estimated pharmacokinetic parameters. Model-based values for CL and V were generated for each patient on the basis of the conditional mean estimate using the final pharmacokinetic model (20). Predicted polymyxin B plasma concentrations for the regimens with mean loading and nonloading doses within the clinical cohort were simulated using the R package Simulx (21). For each scenario, the mean population parameters and intersubject variabilities (i.e., omega values) were used to generate 2,000 PK exposure profiles using the mlxR package. See Supplemental Text S1 in the supplemental material for the mlxR code (22).