Impact of humanized vancomycin infusion on kidney function and kidney injury in a translational rat model.

Allometric dose scaling aims to create isometric exposures between animals and humans and is often employed in preclinical pharmacokinetic/pharmacodynamic models. Bolus dose allometric scaling is the most simple and commonly used strategy in kidney injury studies; however, it is possible to humanize drug exposures. Currently, it is unknown if dose-matched bolus allometric scaling results in similar outcomes to humanized infusions in the vancomycin induced kidney injury model. We utilized a preclinical Sprague-Dawley rat model to compare traditional allometrically scaled dose-matched bolus administration of vancomycin to a computer-controlled and humanized infusion scheme to assess for differences in iohexol-measured kidney function and urinary kidney injury biomarkers. Following 24 hours of vancomycin administration, rats in the humanized infusion group had equivalent area under the curve exposures to animals in the dose-matched bolus group (93.7 mg∙h/L [IQR 90.2 to 97.2] vs. 99.5 mg∙h/L [IQR 95.1 to 104.0], p=0.07). No significant differences in iohexol-measured kidney function nor the urinary kidney injury biomarkers, kidney injury molecule-1, clusterin, and osteopontin, were detected. Administration of intravenous vancomycin as either a humanized infusion or dose-matched bolus resulted in similar vancomycin exposures, but no differences in iohexol-measured GFR and urinary kidney injury biomarkers among male Sprague-Dawley rats.