The impact of recent legislative changes focused on improving our knowledge of drugs used in the treatment !of children is slowly being realized, but current studies have not investigated the differences in drug disposition afforded by disease state. This is most notable for critically ill children, in who changes in organ function, total body water, tissue and plasma proteins, can all affect the disposition and action of therapeutic drugs. The long-term research goal of this proposal is to optimize the safety and efficacy of drugs used in the treatment of critically ill children by bridging our gap in knowledge of the clinical pharmacology of drugs frequently used in these patients. We will use sophisticated pharmacokinetic-pharmacodynamic (PK-PD) modeling techniques and clinical trial simulation to streamline the development and performance of clinical studies. Our central hypothesis is that informative clinical trials can be designed more efficiently when well characterized models that account for sources of variation in pharmacokinetics and pharmacodynamics are utilized. We plan to initially construct select models based on published clinical pharmacologic data, and then perform clinical trials simulations for the design of prospective studies of drugs frequently used in the care of critically ill children. Based on the results of our models and trial simulations, we will then carry forward and perform clinical studies of two frequently used drugs (pentobarbital and dopamine) in critically ill children. lastly, we will integrate results from these clinical studies back into our models to allow for pharmacologically more rational dosing in this difficult to study pediatric population. For this mentored training, two complementary approaches will be pursued. The first will be formal coursework covering a range of topics iintegral to the field of clinical pharmacology. The second approach will be through a mentored clinical and laboratory research program. This intensive didactic and mentored training will allow for the development of a future independent pediatric clinical investigator.
| Zuppa, Athena F; Nicolson, Susan C; Barrett, Jeffrey S et al. (2011) Population pharmacokinetics of pentobarbital in neonates, infants, and children after open heart surgery. J Pediatr 159:414-419.e1-3 |
