What are the pharmacokinetic properties of Polymyxin B, including its route of administration, distribution volume, protein binding, metabolism, clearance, half‑life, and dosing adjustments in renal impairment?

Polymyxin B Pharmacokinetics

Polymyxin B is administered intravenously as the active drug (not a prodrug), with dosing based on body weight; plasma concentrations are not significantly influenced by renal function, and dose adjustments are not required in renal impairment or continuous renal replacement therapy (CRRT). 1

Route of Administration

Polymyxin B is available for intravenous administration as the active drug, distinguishing it from colistin which is administered as the inactive prodrug colistimethate sodium (CMS) 1. The FDA label also describes intramuscular, intrathecal, and topical/ophthalmic routes, though IV is the primary route for systemic infections 2.

Dosing Regimen

Loading Dose

• 2-2.5 mg/kg should be administered to achieve optimal plasma levels on the first day 1
• The loading dose should be given to all patients including those with renal dysfunction 1

Maintenance Dose

• 1.5-3 mg/kg/day divided in 2 doses (every 12 hours) 1
• Continuous infusion may be suitable as an alternative 1
• FDA labeling suggests 15,000-25,000 units/kg/day (approximately 1.5-2.5 mg/kg/day, as 1 mg = 10,000 units) 2

Recent population pharmacokinetic studies suggest fixed dosing may be preferable: a loading dose of 150-200 mg followed by maintenance of 75 mg every 12 hours for patients weighing 50-90 kg achieves optimal target attainment while minimizing nephrotoxicity risk 3.

Distribution

Volume of Distribution

• Large volume of distribution: approximately 30-35 L in critically ill patients 4, 5
• When normalized to body weight: 0.34-0.50 L/kg 6
• Volume increases significantly in certain populations:
  • 60% larger in end-stage kidney disease patients on hemodialysis 4
  • Increased in critically ill patients due to fluid shifts and altered physiology 7

Protein Binding

• High protein binding: 48.8-85.5% in critically ill patients 5, 6
• Binding varies considerably between individuals, contributing to pharmacokinetic variability

Tissue Penetration

• Poor pulmonary penetration: epithelial lining fluid (ELF) to plasma ratio of only 15.7% 5
• Minimal CNS penetration with systemic administration, necessitating intrathecal administration for meningitis 2

Metabolism and Clearance

Clearance

• Total body clearance: 1.55-2.1 L/h in most patients 4, 6, 8
• Not significantly influenced by renal function 1—this is the critical distinguishing feature from colistin
• Clearance is reduced in renal insufficiency (2.1 L/h vs 3.9 L/h in normal function) 8, though the clinical significance remains debated
• Creatinine clearance (CrCL) has been identified as a covariate affecting clearance in population PK models 9, 10

Dialysis Considerations

• Dialysis clearance is minimal: only 5.6-12.2% of total body clearance during CVVHD 6
• Recovery rate from dialysate: approximately 22% 8
• Convective RRT modalities (CVVH, CVVHDF) show increased clearance compared to diffusive modalities (CVVHD) 10

Half-Life

• Extended half-life: approximately 19.6 hours at steady state 5
• Half-life is prolonged by 10 hours in end-stage kidney disease patients on intermittent hemodialysis compared to healthy controls 4
• This relatively long half-life supports twice-daily dosing 1

Dosing in Renal Impairment

The key pharmacokinetic advantage of polymyxin B over colistin is that dose adjustments are NOT necessary in renal impairment or CRRT 1. This represents a major clinical distinction:

Patients with Renal Insufficiency

• Use the same dose as patients with normal renal function 1
• While some studies show decreased clearance in renal insufficiency 8, 9, guideline recommendations maintain that plasma concentrations are not influenced by renal function to a clinically significant degree 1
• The FDA label suggests dose reduction from 15,000 units/kg downward in kidney impairment 2, but this conflicts with more recent evidence-based guidelines

Patients on CRRT

• No dose adjustment necessary—use the same dose as normal renal function 1
• Recommended: loading dose 2-2.5 mg/kg, maintenance 1.5-3 mg/kg/day in 2 doses 1
• Fixed dosing of 100 mg every 12 hours after a 200 mg loading dose is optimal for patients on CVVHD 8

Patients on Intermittent Hemodialysis

• Recent research suggests fixed maintenance dose of 100 mg every 12 hours with standard loading dose 8
• AUC is 58% higher in IHD patients, with 42% lower clearance 4

Safety Considerations

Polymyxin B appears to have lower nephrotoxicity compared to colistin 1. In comparative studies, nephrotoxicity rates were 15.3% with polymyxin B versus 33% with colistin 1.

Clinical Caveats

• Substantial interindividual variability exists in clearance and volume of distribution 10, 7
• Therapeutic drug monitoring (TDM) should be considered when available, particularly in patients with extremes of renal function 8, 10
• Target AUC₀₋₂₄: 50-100 mg·h/L for optimal efficacy and safety 5, 3
• The optimal AUC cutoff for clinical efficacy is 77.27 mg·h/L 5
• Current weight-based dosing may expose some patients to increased nephrotoxicity risk; fixed-dose strategies warrant consideration 3