The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in rats

Abstract

Nephrotoxicity has seriously affected the clinical application of colistin methanesulphonate (CMS). Colistin B methanesulphonate (CMS-E2) is a novel polymyxin developed and aimed to have lower nephrotoxicity. This study aimed to investigate the relationships between pharmacokinetics (PK) and nephrotoxicity of CMS and CMS-E2 and compare the toxicity of the two drugs in rats. Rats were treated intraperitoneally with a single dose of saline, CMS [10, 20 mg/kg of colistin base activity (CBA)], and CMS-E2 (20, 40 mg/kg CBA). An LC-MS/MS method was developed to determine plasma and renal tissue concentrations of CMS/CMS-E2 and colistin/colistin B. The severity of renal injuries was examined both biochemically and histologically. The PK-toxicodynamic (TD) model was evaluated to characterize the PK of CMS/CMS-E2 and colistin/colistin B in plasma as well as its relationship with nephrotoxicity. Creatinine (CR) and blood urea nitrogen (BUN) profiles were described using an indirect link PK-TD model, with linear-effect relationship. Both the slope between colistin or colistin B concentrations in the effect compartment and CR, BUN was significantly lower for CMS-E2 compared with CMS (CR: P = 0.027, BUN: P = 0.043). The concentrations of colistin and colistin B in kidneys were correlated with CR, BUN values, and histologic examination scores. The regression coefficient of CMS-E2 between the colistin B concentrations in renal tissues and CR, BUN values were lower, as well (CR: P = 0.003, BUN: P = 0.001). The renal injuries induced by CMS and CMS-E2 lagged behind the change of plasma colistin or colistin B concentrations and correlated to those in kidneys. CMS-E2 showed significantly lower nephrotoxicity compared to CMS in vivo.

Keywords: Colistin; Colistin B; Colistin methanesulphonate (CMS); Nephrotoxicity; Pharmacokinetic-toxicodynamic; Polymyxins.

Fig. 1

Mean (± SD) plasma concentrations of CMS/CMS-E2 and colistin/colistin B versus time following intraperitoneal administration of CMS at 10, 20 mg/kg CBA and CMS-E2 at 20, 40 mg/kg CBA. CMS colistin methanesulphonate, CMS-E2 colistin B methanesulphonate, CBA colistin base activity.

Fig. 2

Mean (± SD) concentrations of CMS/CMS-E2 and colistin/colistin B in renal tissue versus time following intraperitoneal administration of CMS at 10, 20 mg/kg CBA and CMS-E2 at 20, 40 mg/kg CBA. (The CMS concentration was below the lower limit 6, 8 h after administration of CMS 10 mg/kg CBA and 24 h after administration of CMS 20 mg/kg CBA). CMS colistin methanesulphonate, CMS-E2 colistin B methanesulphonate, CBA colistin base activity.

Fig. 3

Changes of acute kidney injuries over time and comparison between groups. Mean (± SD) plasma values of (A) CR, (C) BUN and (E) SQS versus time following intraperitoneal administration of CMS at 10, 20 mg/kg CBA and CMS-E2 at 20, 40 mg/kg CBA. The peak level of (B) CR, (D) BUN and (F) SQS among control and all dose groups. * below each bar represents the difference between this group and the control group in (B) and (D). Because the SQS in the control group was 0, it was not displayed in (F). *P < 0.05, **P < 0.01, ***P < 0.001. CMS colistin methanesulphonate, CMS-E2 colistin B methanesulphonate, CBA colistin base activity, CR, creatinine, BUN blood urea nitrogen, SQS semiquantitative score.

Fig. 4

PK/TD modeling of plasma PK and biomarkers of CMS and CMS-E2. A, Schematic representation of a one-compartmental PK model in which the hypothetical effect compartment is indirectly linked to the plasma pharmacokinetic compartment (take CMS for example). B, Relationship between CL_CMS, CL_CMS−E2, CL_colistin, and CL_{colistin B} and the value of CR. CMS, colistin methanesulphonate; CMS-E2, colistin B methanesulphonate; CL_CMS, clearance of CMS; CL_CMS−E2, clearance of CMS-E2; CL_colistin, clearance of colistin; CL_{colistin B}, clearance of colistin B; K_a, absorption rate; K_{CMS, colistin}, the rate constant for CMS conversion into colistin; K_e, elimination rate from colistin central compartment to effect compartment; E, level of plasma creatinine and urea nitrogen in CMS and CMS-E2-induced nephrotoxicity; E₀, baseline level of plasma creatinine and urea nitrogen prior to drug administration; S, proportional coefficient between drug concentrations and the effect; C_e, colistin concentrations in effect compartment, CR creatinine.

Fig. 5

Relationship between the renal tissue concentrations of colistin (upper) and colistin B (bottom) and the values of CR, BUN, and SQS (from left to right). CR creatinine, BUN blood urea nitrogen, SQS semiquantitative score.

Fig. 6

The flow chart of study design. CMS colistin methanesulphonate, CMS-E2 colistin B methanesulphonate, CBA colistin base activity, CR, creatinine, BUN blood urea nitrogen. Created with BioRender.com.