Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens.

BACKGROUND: Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients. METHODS: Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted. RESULTS: Twenty-four patients aged 21-87 years received intravenous polymyxin B (0.45-3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10-143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r(2) = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose. CONCLUSIONS: Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.

Pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis.

OBJECTIVES: To evaluate the pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis (CVVHD) after intravenous administration of unadjusted dosage regimens. PATIENTS AND METHODS: Two critically ill patients had eight blood samples collected during a 12 h interval on days 8 and 10 of polymyxin B therapy. Dialysate was collected every hour during the 12 h dosing interval. Polymyxin B binding in plasma was determined by rapid equilibrium dialysis. Concentrations of polymyxin B in plasma and dialysate samples were quantified using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. RESULTS: Respective maximum plasma concentrations in patients 1 and 2 were 8.62 and 4.38 mg/L; total body clearances (scaled linearly by body weight) were 0.043 and 0.027 L/h/kg, respectively, of which 12.2% and 5.62% were dialysis clearance, respectively. The corresponding volumes of distribution of polymyxin B at steady state were 0.50 and 0.34 L/kg, respectively, and protein binding in pooled plasma samples was 74.1% and 48.8%, respectively. CONCLUSIONS: Our findings indicate that the recommended polymyxin B doses should not be reduced for patients on CVVHD.