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Abstract:
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It's often challenging to select dose for Phase III, especially for pediatric program. In this presentation, a Merck compound will be used as an example to illustrate the approach and strategy of the revised dosing of the dose selection. This compound has been approved as a single dose IV regimen in adults. In a Phase IIb dose-ranging pharmacokinetic and pharmacodynamic (PK/PD) study in pediatric patients birth to 17 years of age, an adaptive design was used, which gave us opportunity to review the data with a formal interim analysis after 50% enrollment and revise the dose according if necessary. At the interim, the PK parameters from noncompartmental analysis (NCA) including AUC, Cmax, and Ctrough were log transformed and compared to those in historical adult data via a linear effects model containing fixed effect for age at each dose level. The PK analysis along with exploratory efficacy data showed that the exposure and response with the initial three dose levels were lower than expected for subjects < 12 years old. Inverse regression calibration approach and other statistical methods that can used to predict a more appropriate dose will be explored and discussed in this talk
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