Pediatrics

The fields of clinical pharmacology and drug development have been shaped by adverse events in children. Two great tragedies promulgated changes in the drug regulatory process in the United States: 1) the death of 107 patients (mostly children) due to a sulfanilamide elixir which contained diethylene glycol prompted the first requirement of safety testing for new drug products; and 2) birth defects in babies secondary to maternal use of thalidomide resulted in the requirement that drugs be deemed safe and effective and that safety and efficacy in one population would not infer safety and efficacy in another. Ironically, the changes that came about from these events only served to further limit the testing of new drug products in children. Three factors have limited the quality and quantity of pediatric clinical trials: their classification as a vulnerable population and its attendant ethical constraints and regulatory hurdles, the relatively small size of the pediatric pharmaceutical market which limited industry funding, and the lack of homogeneity in the population due to developmental changes. However, regulatory efforts begun in 1997 have helped fuel an increase in industry-funded pediatric drug research over the past several years. Despite these advances, research in children remains an expensive and complicated endeavor and companies often lack the internal expertise necessary to design and implement these programs.

ICPD scientists have served as a resource for several pharmaceutical companies during the submission of pediatric-related filings to the FDA and our experience in this area spans the full breadth of activities from designing studies in children to analysis of pharmacokinetic-pharmacodynamic (PK-PD) data from such studies and, ultimately, to presentation of such results at regulatory meetings. The main focus of our involvement is centered on assuring that the most appropriate pediatric dose is selected. This is accomplished by integration of pre-clinical PK-PD data and early clinical pharmacokinetic (PK) data to identify dosage regimens that optimize the probability of positive clinical outcomes and minimize the potential of drug toxicities. As early PK data is most often obtained in adults, the final step is to bridge adult PK and PK-PD relationships for safety and efficacy to the known ontogeny of drug disposition in children to define appropriate dosing schemes for drugs used to treat pediatric illnesses.

One Recent Application

Bacillus anthracis has been used as a weapon of bioterrorism. Given that the conduct of clinical trails is not possible and the consequences of inadequate therapy are dire, it is critical to identify the optimal treatments for adult and pediatric patients using in-vitro infection models and PK-PD simulations. The murine- B. anthracis infection model can be used to determine the PK-PD measure most predictive of drug efficacy and the magnitude of exposure necessary for survival. Human population pharmacokinetic models and simulation can then be used to identify dosing regimens with high probabilities of attaining exposures likely efficacious. We utilized this approach to evaluate potential adult and pediatric dosing regimens of gatifloxacin against B. anthracis.

Non-neutropenic female BALB/c mice were challenged by aerosol with between 50 and 100 times the established LD50 (3.4×104 CFU) of a spore preparation from the Ames strain of B. anthracis (gatifloxacin MIC, 0.125 mg/L). Antibiotic treatment was administered to mice to emulate human regimens with several daily doses divided into 8, 12, and 24 hour intervals beginning 24 hours post-challenge. Doses corresponded to AUC0-24 values ranging from 1.875 to 100 mg•hr/L. Analysis of the mouse exposure-response data identified the f AUC0-24:MIC ratio as the PK-PD index that best correlated with survival. A target of 30 was chosen based on its association with >99% maximal effect. Using a population pharmacokinetic model for gatifloxacin in children, developed from a large Phase 1, pediatric, dose ranging study, it was possible to use Monte Carlo simulation to identify the probability of achieving a ratio of 30 for different dosing regimens in children. The regimen tested in Phase 2 and 3 otitis media trials (10 mg/kg daily) results in a probability of PK-PD target attainment of 0.95 or greater for MIC values of 0.5 mg/L or less.

A comparison of the probability of target attainment at various MIC values for the adult dose (400 mg daily; blue line) and the pediatric dose (10 mg/kg daily; red line) is provided in the figure below. The gatifloxacin- Bacillus anthracis MIC distribution is represented by the grey histogram.