Comparing the Population Pharmacokinetics of and Acute Kidney Injury Due to Polymyxin B in Chinese Patients with or without Renal Insufficiency

Abstract

Despite excellent bactericidal effect, dosing adjustment of polymyxin B for patients with renal insufficiency and polymyxin B-related nephrotoxicity is still a major concern to clinicians. The aim of this study was to compare the population pharmacokinetic (PK) properties of polymyxin B in Chinese patients with different renal function and to investigate the relationship between PK parameters and polymyxin B related-acute kidney injury (AKI). A total of 37 patients with normal renal function (creatinine clearance ≥ 80 mL/min) and 33 with renal insufficiency (creatinine clearance < 80 mL/min) were included. In the two-compartment population PK models, the Cl (2.19 L/h vs 1.58 L/h; P < 0.001) and Q (13.83 L/h vs 10.28 L/h; P < 0.001) values were significantly different between the two groups. The simulated AUCss,24h values for patients with normal renal function were higher than those for patients with renal insufficiency. However, the renal dosing adjustment of polymyxin B seemed not to be necessary. Besides, during the treatment, AKI occurred in 23 (32.86%) patients. The polymyxin B AUCss,24h in patients with AKI was significantly higher than that in patients without AKI (108.66 ± 70.10 mg⋅h/L vs 66.18 ± 34.79 mg⋅h/L; P = 0.001). Both the ROC curve and Logistic regression analysis showed AUCss,24h > 100 mg⋅h/L was a good predictor for the probability of nephrotoxicity.

Optimal Empiric Polymyxin B Treatment of Patients Infected with Gram-Negative Organisms Detected Using a Blood Antimicrobial Surveillance Network in China

“… 22 Furthermore, a PMB PPK study found that CL and Q values differed significantly in patients with normal and reduced renal function, whereas the variance and median AUC ss,24h changes remained within a 2-fold range in patients treated with a weight-based maintenance dose, a finding commonly accepted as the threshold justification for dosing adjustment. 18 , 31 Although dosing adjustment may not be necessary in patients with renal impairment, this strategy has been associated with increased toxicity rates in patients with decreased renal function, with over 50% of simulated AUC ss,24h being >100 mg∙h/L. 18 Moreover, weight-based maintenance doses have been associated with increased toxicity in higher-weight patients.…”

“… 18 , 31 Although dosing adjustment may not be necessary in patients with renal impairment, this strategy has been associated with increased toxicity rates in patients with decreased renal function, with over 50% of simulated AUC ss,24h being >100 mg∙h/L. 18 Moreover, weight-based maintenance doses have been associated with increased toxicity in higher-weight patients. 32 , 33 In the present study, a fixed maintenance dose of 60 mg q12h provided sufficient antimicrobial coverage against carbapenem-resistant Gram-negative organisms in patients with renal impairment, along with a relative low risk of toxicity.…”

“…First, the PPK model was developed from 462 plasma samples obtained from 37 normal patients and 33 with reduced renal function. 18 The rich PK properties of PMB may be not fully evaluated, resulting in a bias in simulating PMB concentration. Second, the MIC of PMB against organisms from China may not be representative of the MIC distributions in other regions of the world.…”

“…The PPK data for PMB were obtained from a recently published study on critically ill patients in China, with a two-compartment model used to describe the time-concentration relationship for PMB. 18 In that study, patients were grouped into those with normal renal function (n=37) and renal insufficiency (n=33). The mean creatinine clearance (CrCL) in these two groups were 123.3 mL/min (range, 81.6–315.2 mL/min) and 42.0 mL/min (range, 15.6–77.6 mL/min), respectively.…”

“…In addition, PMB has a narrow therapeutic window, and its nephrotoxicity is a dose‐limiting adverse effect. Based on a pharmacometric meta-analysis of PMB nephrotoxicity, an AUC ss,24h of 100 mg∙h/L was regarded as a predictor of nephrotoxicity, 18 , 22 and a target AUC ss,24h >100 mg∙h/L was defined as a threshold associated with an increased risk of nephrotoxicity. All the simulated dosing regimens were tested to calculate the possibility of clinical cure and toxic effects.…”