Approved drugs are rarely initially studied in "real-world" patients in a manner sufficient to adequately detail their toxicity profile. Thus, an opportunity exists to refine drug dosing schemes even after they are approved by the Food and Drug Administration. Advances in mathematical modeling techniques now allow design of dosing schemes that minimize toxicity in "real-world" patients after the drug exposure-toxicity relationship and the variability of drug exposure in the target population is known. Vancomycin is a prototype drug that is a cornerstone in the treatment of Gram positive infections and represents a preventable cause of Acute Kidney Injury (AKI). Owing to over 50 years of clinical experience, much is known about vancomycin pharmacokinetic (PK) exposure. However, the relationship with the pharmacodynamic (PD) outcome of AKI remains poorly defined. This project seeks as a long term goal to integrate data from validated PK/PD models (in vitro, animal, and human) and human PK studies to construct clinical drug dosing strategies that minimize the probability of antibiotic-exposure related adverse events while maximizing efficacy. The overall objective of this application is to employ vancomycin as a prototype drug that causes AKI to elucidate the PK/PD relationship and identify optimal dosing schemes. The central hypothesis of this research is that the intensity and shape of the vancomycin exposure profile accounts for the onset and the extent of AKI. Our hypothesis has been formulated from observations that AKI occurs with contemporary vancomycin dosing schemes in humans Recent animal studies confirm causality when humanized vancomycin exposures are used. This work expands upon previous clinical studies, in silico studies, and laboratory efforts, and employs well validated techniques to focus on the prevention of drug-induced AKI. Specifically, use of an animal toxicity model will allow for carefully planned permutations of vancomycin exposures and bypass the shortcomings of prior clinical analyses where PK/PD endpoints have not been discerned because of homogenous human dosing schemes. The rationale that underlies the proposed research is that the drug exposure-toxicity link must be clearly defined before optimal human regimens can be designed. This application will address two specific aims.
In Aim #1, the vancomycin exposure profile that causes acute kidney injury will be determined by 1) employing carefully controlled dose-range and dose-fractionation studies in rats and 2) measuring AKI with novel biomarkers and traditional histopathology.
In Aim #2, mathematical probability modeling will be conducted with Monte Carlo Simulations that incorporate 1) known vancomycin exposure variability in critical care patients and 2) identified thresholds for vancomycin induced AKI and 3) targets for vancomycin efficacy. We expect that the proposed work will lead to the outcome of vancomycin dosing schemes that minimize AKI while maximizing efficacy for "real-world" patients. This contribution is expected to be significan since optimizing drug therapies to avoid preventable adverse events is the first step to improving the safety of drugs already available in the market.
The proposed research is relevant to public health because it is estimated that each year 342,000 critically ill Americans will experience acute kidney injury directly due to a drug insult. Many of these events are preventable, and the cost is formidable at $4 billion dol- lars annually. Improving drug dosing schemes to mitigate vancomycin induced kidney injury will advance the NIH mission to protect and improve patient health and further advance the FDA Center for Drug Evaluation and Research's (CDER) Safety First/Safe Use initiative to address significant post-market safety issues as the highest priority.