Sepsis is the leading cause of deaths in pediatric intensive care units. The disposition of drugs administered during sepsis are impacted by sepsis-associated pathophysiological changes. However, the exact impact of how these changes influence the pharmacokinetics (PK) of antimicrobials, the mainstay of therapy, is unknown. This knowledge gap places this population at a substantial risk for treatment failures if dose adjustments are not made to accommodate these PK differences. This research will focus on quantifying the pathophysiological changes of sepsis that alter the disposition of renally cleared antimicrobials, using cefepime as a candidate drug. The overall goal of this proposal is to individualize cefepime dosing by quantifying sepsis-associated pathophysiological changes and individual subject covariates that impact cefepime disposition, which will then be incorporated into a model-based dosing strategy for the attainment of target concentrations. The proposed studies during the K99 will collect cefepime PK samples and quantify sepsis-associated physiological changes in renal function using Doppler imaging and physical assessments. This data will then be analyzed using population nonlinear mixed effects modeling. The proposed research in the K99 will provide me with experience in clinical trial design, implementation, and analysis as well as an understanding of the ethical considerations of pediatric clinical research. These are skills that I have not yet had an opportunity to learn, and are essential to becoming an independent pediatric clinical pharmacologist. The proposed studies during the R00 will adapt and incorporate the results of the K99 in order to develop a physiologically based PK model for pediatric sepsis. The model will then be evaluated in a prospective clinical trial using a dosing regimen derived from model simulations and the dose will be individualized for each patient using a Bayesian analysis to assess the feasibility of personalizing doses at the bedside. Additionally, results from this trial will also be incorporated to update the model for the population as a whole. The results of this proposal will help establish a ?virtual critically ill child? model which can be used for renally cleared antimicrobials. Applying this model in the clinic will personalize dosing to improve safety and efficacy in children with sepsis. The environment and infrastructure at The Children's Hospital of Philadelphia supports integrating research into clinical care, making it the ideal location for the proposed research. The mentoring team for this grant has been formed with experts in the fields of critical care, pediatric pharmacology, and pharmacometrics. The career development plan includes extensive training in advanced pharmacometrics, human subjects protection, research ethics, clinical research development, and pediatric critical care pharmacology through hands-on research and didactics. This training plan and mentorship will help build the foundations that will lead to a successful career as an independent researcher and help me transition to a tenure-track faculty position.
Life-threatening infections in children continue to have a high morbidity and mortality rate and there is little known about how this affects the way a body handles drugs that are prescribed in critical conditions. This study will use a prospective, observational trial to investigate these changes in order to develop a model to predict the dose of drugs required for eradicating the infection. The ultimate goal of the project is to develop a ?virtual critically ill child? that can be used to personalize dosing throughout the extremes of organ dysfunction in these very sick children.
