Polymyxin B Pharmacokinetics in Adult Cystic Fibrosis Patients

Abstract

OBJECTIVES: Polymyxin B pharmacokinetics (PK) in adults with cystic fibrosis (CF) are not well described. The goals of this pilot study were to identify a PK model for patients with CF receiving polymyxin B with exploration of covariate relationships of the PK parameters, to compare polymyxin B PK parameters in adults without CF, and to probe exposures associated with different dosing schemes through simulation. METHODS: Adult patients with CF treated with polymyxin B at New York-Presbyterian Hospital had PK samples measured by liquid chromatography-mass spectrometry (MS)/MS. Multiple PK models were fit utilizing Pmetrics for R. Model covariates considered included: age, total body weight, creatinine clearance, albumin, and body mass index. PK parameters in CF patients were compared with PK parameters for 53 adults without CF who were receiving polymyxin B from the same institution. Simulations with target exposure (area under the curve)/minimum inhibitory concentration (MIC) of 20 mg*L/h were conducted for different dosing schemes and MIC ranges. MAIN RESULTS: Nine patients with CF received between 58 and 240 mg of polymyxin B (median 1.47 mg/kg/dose [IQR (1.43-1.65)]). A two-compartment model adjusting polymyxin B clearance for patient CrCl was better than a standard two-compartment model (p=0.004) in CF patients. When compared to PK parameters for patients without CF, PK parameters of polymyxin B in CF were similar (p>0.05). Simulations for plasma concentrations showed all regimens performed adequately at MICs between 0.03125 and 0.125 mg/L but not at increasing MICs of 1 and 2 mg/L. CONCLUSIONS: In this pilot study of polymyxin B PK in adults with CF, the PK parameters of polymyxin B were mostly similar to adults without CF. We observed a potential association between CrCl and polymyxin B clearance, which stands in contrast to the general adult population. However, this observation requires further study. Additional studies focusing on optimal and safe polymyxin B dosing in CF are needed.