(T1230-12-68) Formulation of PEGylated Liposomes to Reduce Vancomycin Induced Kidney Injury: A Rat Study

Purpose: Vancomycin is a commonly used antibiotic in hospital setting especially against Methicillin resistant staphylococcus aureus (MRSA). Kidney injury is a major adverse event of vancomycin in adults. The drug concentration, specifically area under the concentration curve, predicts kidney injury in adults receiving vancomycin. To reduce vancomycin induced nephrotoxicity, we have successfully encapsulated vancomycin in polyethylene glycol coated liposomes (PEG-VANCO-lipo). We have previously carried out in vitro cytotoxicity studies on kidney cells using PEG-VANCO-lipo and found it to be minimally toxic compared to the standard vancomycin. In this study we have dosed male adult rats with PEG-VANCO-lipo or free vancomycin and compared plasma vancomycin concentrations and KIM-1 as an injury biomarker in rat urine.

Methods: Sprague Dawley rats (350 ± 10 g) were administered vancomycin (n=3) or PEG-VANCO-lipo (n=3) 150 mg/kg/day for 3 days using an MTD-IV infusion in the left jugular vein catheter. Blood was collected for plasma at 15, 30, 60, 120, 240 and 1440 minutes after the first and the last MTD-IV. Urine was collected 0-2, 2-4, 4-8, and 8-24 hours after the first and the last IV infusions using metabolic cage. Body weights were recorded pre-dose and at 72 hours after the last dose on day 1-4. The animals were observed, and mortality noted daily for three days after the last compound administration. Vancomycin was quantified in plasma by LC-MS/MS. Urinary KIM-1 analysis was done by using an ELISA kit (R&D system). Three days after the last dose, under terminal anesthesia with IP ketamine (65-100 mg/kg) and xylazine (7-10 mg/kg), rats were euthanized.

Results: The mean body weights of rats on days 1-4 between the two groups free vancomycin vs. PEG-VANCO-lipo were not statistically different (p >0.05, t test) on day 1-4. Vancomycin urine concentrations and KIM-1 (Figure 1) were lower on day 3 in PEG-Vanco-lipo group compared to free vancomycin group but was not statistically significant (p >0.05, t test). There was a significant reduction in plasma vancomycin concentration on day 1 (data not shown) and day 3 (Figure 2 P ≤ 0.01, t test) in free vancomycin group compared to PEG-VANCO-lipo group. This indicates that the PEG-VANCO-lipo is able to keep vancomycin more in plasma as opposed to kidneys, which is site of its toxicity.

Conclusion: Vancomycin loaded PEGylated liposomes have a great potential in reduction of nephrotoxicity as noted by a trend of decreasing KIM-1, while increasing the concentration in plasma (as opposed to urine).

Acknowledgements: Funding provided by intramural grant of MUW-CPG provided to MJ


Figure 1: Mean urine KIM-1 values in ng/mL of rats after treatment with either free vancomycin or PEG-VANCO-lipo. ns=non significant.


Figure 2: Mean plasma vancomycin levels (ng/mL) rats after treatment with either free vancomycin or PEG-VANCO-lipo. *P ≤ 0.05, **P ≤ 0.01***P ≤ 0.001, t test.