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. 2024 Apr 12;13(4):354.
doi: 10.3390/antibiotics13040354.

Pharmacokinetics and Nephrotoxicity of Polymyxin MRX-8 in Rats: A Novel Agent against Resistant Gram-Negative Bacteria

Xingyi Qu  1   2   3 , Chenxue Guo  1   2   3 , Shaojun Liu  4 , Xin Li  1   2   3 , Lin Xi  1   2   3 , Xiaofen Liu  1   2   3 , Jing Zhang  1   2   3   5
Affiliations

Pharmacokinetics and Nephrotoxicity of Polymyxin MRX-8 in Rats: A Novel Agent against Resistant Gram-Negative Bacteria

Xingyi Qu et al. Antibiotics (Basel). .

Abstract

MRX-8 is a novel polymyxin for carbapenem-resistant Gram-negative infections that has been recently evaluated in Phase I clinical trials. Herein, its pharmacokinetics (PK) and nephrotoxicity in rats are reported for the first time. This study aimed at pre-clinical PK and safety assessments. An LC-MS/MS method was developed to determine concentrations of MRX-8 and its major deacylation metabolite, MRX-8039, in rat plasma. Animals were administered a single dose of MRX-8 (2, 4, 6, and 8 mg/kg) or comparator polymyxin B (PMB) (4 and 8 mg/kg) to compare the kidney injury known for the polymyxin drug class. Nephrotoxicity was evaluated using serum creatinine, blood urea nitrogen (BUN) biomarkers, and renal histopathology. In rats, MRX-8 displayed linear PK within the range of 2-8 mg/kg, with approximately 4% of MRX-8 converted to MRX-8039. MRX-8 induced only mild increases in serum creatinine and BUN levels, with an apparent decrease in nephrotoxicity within 24 h, in contrast to PMB, which exhibited a significant and more persistent toxicity. Additional nephrotoxicity biomarkers (plasma NGAL and urinary NGAL, KIM-1, and TIMP-1) have confirmed attenuated MRX-8 kidney injury. Histopathology has revealed significantly greater cellular/tissue toxicity for PMB as compared to MRX-8 (variances of p = 0.008 and p = 0.048 vs. saline control, respectively). Thus, MRX-8 induces a mild and reversible kidney injury in rats compared to PMB. These data support a continued evaluation of the novel polymyxin in human trials.

Keywords: MRX-8; MRX-8039; nephrotoxicity; pharmacokinetics; polymyxins.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Structures of MRX-8, metabolite MRX-8039, and polymyxin B. (a) Chemical structures and transformation of MRX-8 and MRX-8039; (b) Chemical structure of polymyxin B.
Figure 2
Figure 2
Typical chromatograms of MRX-8, MRX-8039, and IS spiked in rat plasma. (a) Chromatogram of MRX-8 under parent ion monitoring mode; (b) chromatogram of MRX-8039 under parent ion monitoring mode; (c) chromatogram of MRX-8 in blank plasma without spiking MRX-8 and MRX-8039; (d) chromatogram of MRX-8039 in blank plasma without spiking MRX-8 and MRX-8039; (e) chromatogram of MRX-8 in plasma at LLOQ level; (f) chromatogram of MRX-8039 in plasma at LLOQ level; (g) chromatogram of MRX-8 in plasma sample after subcutaneous administration of MRX-8; (h) chromatogram of MRX-8039 in plasma sample after subcutaneous administration of MRX-8; (i) chromatogram of IS spiked in plasma (20 mg/L).
Figure 3
Figure 3
The concentration–time curves of MRX-8, MRX-8039, and PMB in rat plasma after subcutaneous administration. (a) Concentration–time curves of MRX-8. (b) Semi-logarithmic concentration–time curves of MRX-8. (c) Concentration–time curves of MRX-8039. (d) Semi-logarithmic concentration–time curves of MRX-8039. (e) Concentration–time curves of PMB. (f) Semi-logarithmic concentration–time curves of PMB. The green, yellow, blue, and pink lines indicate subcutaneous administration of 2 mg/kg, 4 mg/kg, 6 mg/kg, and 8 mg/kg MRX-8, respectively. The light and dark blue lines indicated subcutaneous administered PMB 4 mg/kg and 8 mg/kg, respectively. The error bars indicate the corresponding standard deviation (n = 5). PMB: polymyxin B.
Figure 4
Figure 4
The creatinine and BUN levels after subcutaneous administration of saline, MRX-8, and PMB at 8 h and 24 h. (a) Creatinine levels at 8 h. (b) Creatinine levels at 24 h. (c) BUN levels at 8 h. (d) BUN levels at 24 h. Control: saline group; PMB: polymyxin B; BUN: blood urea nitrogen; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.
Figure 5
Figure 5
The NGAL levels in plasma and NGAL, KIM-1, and TIMP-1 levels in urine at 24 h after subcutaneous administration of saline, MRX-8, and PMB of 4 mg/kg and 8 mg/kg. (a) NGAL levels in plasma; (b) NGAL levels in urine; (c) KIM-1 levels in urine; (d) TIMP-1 levels in urine. NGAL: neutrophil gelatinase-associated lipocalin; KIM-1: kidney injury molecule-1; TIMP-1: tissue inhibitor of metalloproteinase-1; control: saline group, PMB: polymyxin B; * p < 0.05, ** p < 0.01.
Figure 6
Figure 6
PAS staining of kidney tissue after 24 h of administration with saline, MRX-8, and PMB. (a) Experimental design. (b) Kidney tissue after saline administration. (c) Kidney tissue for MRX-8 at 4 mg/kg. (d) Kidney tissue for PMB at 4 mg/kg. (e) Kidney tissue for MRX-8 at 8 mg/kg. (f) Kidney tissue for PMB at 8 mg/kg. Blue arrows: brush border loss; black arrows: basal membrane exposure; red arrows: nuclear shrinkage; green arrows: tubular formation.
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