Pharmacokinetics and Renal Disposition of Polymyxin B in an Animal Model

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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...

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

Manchandani

Zhou

Babic

et al. 2017

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“…In experimental animals with transient renal impairment, similar drug exposures were observed after receiving the same dose (in mg/kg) despite drastic differences in renal function (9,10). These data were consistent with human data, suggesting minimal renal clearance of polymyxin B (7,11).…”

Section: Discussionsupporting

confidence: 80%

Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency

Thamlikitkul

Dubrovskaya

Manchandani

et al. 2017

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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,

“…The exact mechanism of AKI caused by PMB is still not well characterized. Animal models suggest that nephrotoxicity is caused by the accumulation of PMB in renal proximal tubule cells, which may lead to extensive injury and acute tubular necrosis (15)(16)(17). The impacts of dosing frequency on the accumulation of PMB in renal tissue, the severity of the renal lesions, and the onset of nephrotoxicity were specifically examined in a dose fractionation study by Abdelraouf et al in which two groups of rats were administered the same total daily doses of PMB but with the different dosing frequencies (2).…”

Section: Discussionmentioning

confidence: 99%

Nephrotoxicity Associated with Intravenous Polymyxin B Once- versus Twice-Daily Dosing Regimen

Okoduwa

Ahmed

Guo

et al. 2018

Nephrotoxicity is a known adverse effect of polymyxin B (PMB). Animal data suggest that once-daily dosing may reduce the rate and delay the onset of acute kidney injury (AKI). In a multicenter retrospective study, we evaluated adult patients with a creatinine clearance (CrCl) of ≥30 ml/min who received ≥48 h of PMB therapy. The primary endpoint was the difference in rate of AKI comparing once- and twice-daily PMB dosing. The secondary endpoints included the time to AKI and the recovery of renal function. Of 273 eligible patients, 100 from each group were matched on the basis of propensity scores. In the matched groups, nephrotoxicity, defined according to risk, injury, failure, loss, and end-stage renal disease (RIFLE) criteria, was more frequent with once- than with twice-daily dosing (47% versus 17%, respectively; = 0.0005). After adjusting for residual differences by multivariate conditional logistic regression, once-daily dosing was more likely to result in nephrotoxicity (adjusted odds ratio, 2.5; 95% confidence interval [CI], 1.413 to 4.541; = 0.002). Among 64 patients who developed AKI, the median onsets were similar between the groups (7 days with once versus 6 days with twice-daily dosing, = 0.095). Of 37 patients who had their serum creatinine evaluated subsequently, 29/37 (78%) had recovery of renal function. No patient required renal replacement therapy. Our findings suggest that AKI is significantly more common with PMB once daily than with twice-daily dosing with no difference in time to AKI. A prospective randomized study is warranted to validate these results.