Population Pharmacokinetic and Exposure-Response Analysis of Vancomycin Nephrotoxicity in Cystic Fibrosis Patients

Acute pulmonary exacerbations (APE) in persons with cystic fibrosis (PwCF) are associated with a reduction in long-term pulmonary function. Vancomycin is recommended as first-line treatment of methicillin-resistant Staphylococcus aureus -APE in PwCF. While vancomycin poses a significant risk of nephrotoxicity, the relationship between vancomycin exposure and nephrotoxicity in PwCF has not been characterized.

We aimed to establish the relationship between vancomycin exposure and onset of nephrotoxicity in PwCF, and to identify predictors of nephrotoxicity.

This was a retrospective study among 52 adults PwCF. Nephrotoxicity events were defined based on the RIFLE criteria, as a serum creatinine increase of 1.5 times from baseline or a ≥ 25% decrease in glomerular filtration rate. A population pharmacokinetic (popPK) model was used to derive exposure measures (i.e., area-under the concentration-time curve (AUC)).

A total of 590 vancomycin serum concentrations were available for analysis. A one-compartment model best describes vancomycin pharmacokinetics. Creatinine clearance was included as a significant covariate in the clearance. The popPK model allowed quantification of cumulative AUC (AUC_cum) and AUC₂₄ values, and AUC normalized (AUC_norm) and cumulative dose were further calculated. Each variable of interest was used to fit a generalized linear mixed-effects (GLM) model. The GLM model identified AUC_cum as a significant predictor of vancomycin nephrotoxicity (p < 0.01). Additionally, patients with more than one dosing occasion were significantly more likely to experience nephrotoxicity (p < 0.01). Based on the final AUC_cum model, the odds of experiencing a nephrotoxicity event increased by 32.6% (95% CI: 11.0%-58.4%) for each doubling of AUC_cum.

Our results demonstrate an association between increased vancomycin exposures and risk of nephrotoxicity. This study provides a foundation for optimizing personalized vancomycin dosing strategies in PwCF to balance efficacy and nephrotoxicity risk.