Starting dose Selection
The information for starting dose in phase 1 pediatrics studies was obtained for 37 WRs. The approaches for starting dose selection generally fall in two categories: empirical, and PK modeling and simulation. A summary of methods used for each approach by disease type is shown in Table 5. Majority of the program used the empirical approach of selecting a starting dose equivalent to 100% (most common for hematological malignancy) or ~80% (most common for solid tumor) of body size adjusted adult dose, while 7 programs used 50-70% of adult MTD or RP2D to initial their phase 1 dosing-finding studies. As a comparison, PK modeling and simulation was used to identify the starting dose in pediatric patients for 7 drugs. This approach typically includes allometric scaling of adult PK parameters (ie, clearance and volume of distribution) based on body weight in children, and account for developmental factors such as organ and enzyme maturation where ontogeny functions are added for the dose projection. For one program, non-clinical data in murine model was also used to inform the starting dose selection for a combination therapy, along with data from ealier monotherapy study in pediatrics.
TABLE 4: Methods for starting dose selection in pediatric oncology studies in response to written requests initiated since 2001.