Sean N Avedissian1, Cristina Miglis1, Christine J Kubin2,3, Nathaniel J Rhodes1, Michael T Yin3, Serge Cremers4, Michelle Prickett5, Marc H Scheetz1. 1. Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Downers Grove, Illinois. 2. Department of Pharmacy, NewYork-Presbyterian Hospital, New York City, New York. 3. Division of Infectious Diseases, Columbia University Irving Medical Center, New York City, New York. 4. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York City, New York. 5. Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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.
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.
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