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.