Project I """"""""Colistimethate Dose Optimization in Infants and Children This project is designed to determine the age-dependent changes in pharmacokinetics of colistimethate (the infused methane-sulfonated pro-drug) and colistin in pediatric patients from full term infants to adolescents. We believe that the developmental changes in drug handling of colistimethate and colistin are large enough to warrant different dosing guidelines in pediatric sub-populations. By measuring Cmax, t1/2, Vd, CL and AUC, and by using population analysis of data derived from sparse plasma sampling techniques, and assessing the covariates of age, weight, body surface area and renal function, we will successfully be able to describe the effective and safe dose required for clinical and microbiologic cure in each of the different pediatric age groups, based on exposures studied in both adults and in experimental animals. By analyzing the safety of colistimethate and colistin post-dosing, with particular attention to a wide range of renal toxicity markers, from the standard assays of urinary creatinine and albumin, to more sophisticated markers of renal injury, including transmembrane tubular protein kidney injury molecule-1 (KIM-1), beta2-microglobulin, retinal B protein, and urinary N-acetyl-beta-D-glucosaminidase (NAG). We hope to create a detailed description of the characteristics of renal injury that may occur with colistimethate and colistin, by pediatric age group, to better understand the risks inherent in the therapeutic use of this agent. Finally, by using age-group specific population PK variation in drug exposure, together with published susceptibility data for Gram-negative pathogens to colistin, we will perform Monte Carlo simulation in each age group to assess specific targeted drug exposures required for cure. This is designed to provide sufficient exposure to achieve a high target attainment rate, while minimizing toxicity from unnecessarily high drug exposure.
As antimicrobial resistance increases in nosocomial pathogens, hospital-acquired pediatric infections are increasingly difficult to treat. We propose to analyze and model the developmentally-driven single-dose pharmacokinetics and renal safety a drug of last resort for multi-drug resistant Gram-negative pathogens, colistin, for which virtually no pediatric data currently exist.
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