Polymyxin B is used as a last treatment resort for multidrug-resistant Gram-negative bacterial infections. The objectives of this study were to examine the population pharmacokinetics of polymyxin B and investigate factor(s) influencing pharmacokinetic variability. Four serial blood samples each were collected from 35 adult patients at steady state. The concentrations of individual polymyxin B components were analyzed using a validated liquid chromatography / tandem mass spectrometry assay and combined to derive total concentrations. A maximum likelihood expectation maximization approach was used to fit the data. Various demographic variables were investigated as potential covariates for clearance and volume of distribution (V ) using linear regression analysis. A one-compartment model fit to the data satisfactorily (r = 0.96). The best-fit mean ± SD for clearance and V were 2.5 ± 1.1 L/h and 34.3 ± 16.4 L, respectively. Creatinine clearance was found to be a statistically significant covariate of clearance, but the magnitude was deemed clinically insignificant.

Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CL CR ] Ն 80 ml/min) at baseline, whereas 14 had renal insufficiency (CL CR Ͻ 80 ml/min). The mean AUC of polymyxin B Ϯ the standard deviation in the normal renal function cohort was 63.5 Ϯ 16.6 mg·h/liter compared to 56.0 Ϯ 17.5 mg·h/liter in the renal insufficiency cohort (P ϭ 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 Ϯ 7.0 mg·h/liter versus 29.7 Ϯ 11.2 mg·h/liter, P ϭ 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.KEYWORDS polymyxins, dosing adjustment, drug exposure P arenteral polymyxins (polymyxin B and polymyxin E [colistin]) have become one of the most important antibiotics for therapy of extensively drug-resistant Gramnegative bacterial infections over the past decade, including infections caused by carbapenem-resistant nonfermenters and carbapenem-resistant Enterobacteriaceae. The similarities and differences between polymyxin B and colistin have been reviewed elsewhere (1). Polymyxin B has been increasingly used due to the active drug form used, more straight-forward dosing, more favorable pharmacokinetics, and potentially lower incidence of nephrotoxicity than colistin (2, 3). Current U.S. Food and Drug Administration-approved prescribing information recommends polymyxin B dosing adjustment in patients with renal insufficiency (package inserts from Bedford Laboratories,

Despite dose-limiting nephrotoxicity concerns, polymyxin B has resurged as the treatment of last resort for multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic, and nephrotoxic properties of polymyxin B still are not thoroughly understood. The objective of this study was to provide additional insights into the overall biodistribution and disposition of polymyxin B in an animal model. Sprague-Dawley rats were dosed with intravenous polymyxin B (3 mg/kg of body weight). Drug concentrations in the serum, urine, bile, and tissue (brain, heart, lungs, liver, spleen, kidneys, and skeletal muscle) samples over time were assayed by a validated methodology. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. The mean renal tissue/serum polymyxin B concentration ratios were 7.45 (95% confidence interval [CI], 4.63 to 10.27) at 3 h and 19.62 (95% CI, 5.02 to 34.22) at 6 h postdose. Intrarenal drug distribution was examined by immunostaining. Using a ratiometric analysis, proximal tubular cells showed the highest accumulation of polymyxin B (Mander's overlap coefficient, 0.998) among all cell types evaluated. Less than 5% of the administered dose was recovered in urine over 48 h, but all 4 major polymyxin B components were detected in the bile over 4 h. These findings corroborate previous results that polymyxin B is highly accumulated in the kidneys, but the elimination likely is via a nonrenal route. Biliary excretion could be one of the routes of polymyxin B elimination, and this should be further explored. The elucidation of mechanism(s) of drug uptake in proximal tubular cells is ongoing.T he emergence of multidrug-resistant bacterial infections has become a medical crisis worldwide (1, 2). Infections caused by Gram-negative bacteria, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp., are extremely challenging to treat (3-6). These infections also are associated with high rates of mortality and morbidity (7,8). Moreover, there are few new antibacterial agents available in the clinical drug development pipeline for these life-threatening infections. Consequently, this has led to the revival of old antibiotics, such as the polymyxins, as the treatment of last resort for infections caused by multidrugresistant Gram-negative pathogens (9-13).Polymyxins (primarily polymyxin B and polymyxin E [colistin]) are cyclic polypeptide antibiotics isolated from Bacillus polymyxa (14). Commercially available polymyxin B is a mixture of several related analogs, primarily polymyxin B1, B2, and B3 and isoleucine B1 (15, 16). Polymyxin B first became available for clinical use in the 1950s, but its clinical use has been limited largely due to its nephrotoxic potential.Despite being available for clinical use for more than 50 years, there is still a paucity of published reports correlating the pharmacokinetics of polymyxin B with its toxicity profile. Furthermore, we lack a thorough understanding of the biodistribution pattern, cel...

Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 Ϯ 0.4 g/g, 9.9 Ϯ 1.5 g/g, and 21.7 Ϯ 4.8 g/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. KEYWORDS Polymyxin B, renal drug concentration, megalin, polymyxins T here is a renewed interest in the clinical use of polymyxins due to the increased prevalence of infections caused by multidrug-resistant Gram-negative bacteria (1). Many currently available antibiotics are no longer effective against these resistant bacterial strains. Additionally, the situation is further exacerbated by the limited number of new antibacterial agents in the advanced drug development pipeline. Consequently, the polymyxins have emerged as the last treatment resort against these life-threatening infections.Polymyxins (polymyxin B and polymyxin E [colistin]) are cyclic polypeptide antibiotics which were available for clinical use in the 1950s. However, the clinical use of polymyxins was considerably reduced in the early 1970s due to concerns about nephrotoxicity (2-4). Despite being available for decades, the correlation between the pharmacokinetics and toxicodynamic profiles of polymyxin B is still not thoroughly understood. This knowledge gap often hinders the optimal clinical use of polymyxin B. There is evidence suggesting that polymyxin B is not eliminated through the renal route (5, 6). However, pharmacokinetic studies have reported preferential accumulation and prolonged residence of polymyxin B in rat kidneys (7,8). Several studies have also reported a daily dose of polymyxin B as an independent risk factor associated with...

An impaired renal function, including acute and chronic kidney disease and end-stage renal disease (ESRD), can be the result of ageing, certain disease conditions, the use of some medications or as a result of smoking. In patients with renal impairment (RI), the pharmacokinetics (PK) of drugs or drug metabolites may change and result in increased safety risks or decreased efficacy. In order to make specific dose recommendations in the label of drugs for RI patients, a clinical trial may have to be conducted or, when not feasible, modelling and simulations approaches such as population PK modelling (PopPK) or physiologically-based PK (PBPK) modelling may be applied. This tutorial aims to provide an overview of the global regulatory landscape and a practical guidance for successfully designing and conducting clinical RI trials or, alternatively, on applying modelling and simulation tools to come to a dose recommendation for RI patient in the most efficient manner.