Table 4.

Limitations and challenges in the application of the CRD methodology

The method requires knowledge of the appropriate pharmacokinetic metric to match in the back-extrapolation. In some cases, this can be difficult to determine.
Appropriate translation of dose schedules is an ongoing area of investigation. This is particularly challenging when dosing holidays are involved.
The methodology does not account for differences in the growth rates of nonclinical tumors relative to clinical tumors, which may be a factor in translating dose schedules.
Appropriately characterizing the PPB and deciding when to utilize total drug concentrations (e.g., with highly bound drugs) versus free drug concentrations can be challenging.
Drug–drug interaction in combination studies needs to be addressed on a case-by-case basis.
The methodology should be applied with some caution to mAbs and macromolecular compounds as plasma may not be a good surrogate for tumor concentrations in these cases.