The Pharmacodynamic-Toxicodynamic Relationship of AUC and CMAX in Vancomycin Induced Kidney Injury in an Animal Model

Abstract

BackgroundVancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear.MethodsSprague-Dawley rats received IV vancomycin doses of 300mg/kg/day and 400mg/kg/day, divided once, twice, thrice or 4xdaily (i.e., QD, BID, TID or QID) over 24-hours. Up to 8-samples were drawn during the 24-hour dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via LC-MS/MS. Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e. AUC0-24h, CMAX0-24h,) were calculated for each rat, and PK-TD relationships were discerned.ResultsA total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed vs. predicted concentrations, R2=0.96). KIM-1 values were greater in QD and BID groups (P-values: QD vs TID:<0.002, QD vs QID:<0.004, BID vs TID:<0.002, and BID vs QID:<0.004). Exposure–response relationships were observed between KIM-1 vs CMAX0–24h and AUC0-24h (R2□=□ 0.7 and 0.68). Corrected Akaike’s information criterion showed CMAX0-24h as most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (−5.28 versus −1.95).ConclusionsWhile PK-TD indices are often inter-correlated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.

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“…Vancomycin, the most commonly used antimicrobial agent globally, induces renal toxicity (Avedissian et al, 2021). It was shown that vancomycin (200 mg/kg, given i.p.…”

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“…Vancomycin induced kidney injury (VIKI) is a concentration-driven process, with area under the concentration curve (AUC) and maximum concentrations best correlating with the extent of kidney damage. (8)(9)(10)) Studies indicate that rates of VIKI were approximately 5-7% when troughs were maintained between 5-10 mg/L as the standard of practice. (27,43,46) With the publication of the 2009 consensus vancomycin guidelines that promoted more aggressive dosing (i.e.…”

“…In particular, the availability of a reliable and accurate pre-clinical VIKI model will identify vancomycin dosing schemes associated with the lowest risk of VIKI, determine if ameliorating agents can minimize the risk of VIKI with vancomycin exposures required for efficacy, and assess populations in which vancomycin should be avoided (e.g., those receiving other nephrotoxic agents). Our group has utilized a pre-clinical rat model that describes the risk of VIKI as a function of the intensity of vancomycin exposure (9,31,34,39). While our model demonstrates that there is a clear relationship between vancomycin AUC and VIKI in rats, we have yet to determine if our model bridges to humans.…”