Pharmacokinetic study of polymyxin B in healthy subjects and subjects with renal insufficiency

Abstract

Polymyxin B is a viable option for treating antibiotic-resistant infections; however, current data on its pharmacokinetics, particularly in patients with renal insufficiency, remain inconclusive and necessitates further investigation. To address this gap, we conducted an open-label, single-center, single-dose, parallel-group pharmacokinetic study. Participants received an intravenous dose of 0.75 mg/kg of polymyxin B and were categorized based on their renal function: those with normal function (creatinine clearance [CLcr] ≥ 90 mL/min), mild renal insufficiency (CLcr 60-89 mL/min), and end-stage kidney disease patients on intermittent hemodialysis (IHD) (CLcr < 10 mL/min). The pharmacokinetic parameters assessed included the area under the curve (AUC), maximum concentration (C_max), clearance rate (CL), volume of distribution (Vz), and half-life (t_1/2). Results indicated that subjects with mild renal insufficiency exhibited pharmacokinetic profiles similar to healthy individuals. Nevertheless, in patients undergoing long-term IHD, we observed significant differences: the AUC was 58% higher, C_max was 29% lower, CL was 42% lower, Vz was 60% larger, and t_1/2 was extended by 10 h compared to healthy controls. Secondary outcomes revealed good tolerability of polymyxin B across all groups, with no serious adverse effects related to renal function. In summary, while kidney function may have a slight impact on the pharmacokinetic of polymyxin B, it does not compromise the drug's therapeutic effectiveness.

FIGURE 1

Schema of patient enrolment in the study. Arm 1 (normal renal function group): Subjects with CLcr ≥ 90 mL/min. Arm 2 (mild renal insufficiency group): Subjects with CLcr between 60 and 89 mL/min. Arm 3 (long‐term IHD group): Subjects with end‐stage kidney disease receiving IHD therapy three times a week. CLcr, creatinine clearance; IHD, intermittent hemodialysis.

FIGURE 2

Arithmetic mean plasma concentrations–time profiles of polymyxin B (a) Linear‐linear plot. (b) Semi‐log plot. Arm 1, normal renal function group; Arm 2, mild renal insufficiency group; Arm 3, long‐term intermittent hemodialysis group.

FIGURE 3

Relationship between CLcr and (a). C _max (b). CL (c). AUC_0‐inf (d). AUC_0‐last. Arm 1, normal renal function group; Arm 2, mild renal insufficiency group; Arm 3, long‐term intermittent hemodialysis group; AUC_0‐inf, area under the plasma concentration versus time curve from time 0 extrapolated to infinity; AUC_0‐last, area under the plasma concentration versus time curve from time 0 to the last measurable concentration; CL, clearance; CLcr, creatinine clearance; C _max, maximum observed plasma concentration.