Review Khot, Sharma & Shah
A PK PD Kill Growth Tumor
B PK PD Transduction Growth Tumor Kill Signal Cell death C PK PD Kill Growth Tumor Tumor Tumor Transit compartments
Figure 6. PD models for antibody–drug conjugates. (A) The direct kill model. This model assumes that the cancer cells die immediately upon exposure to the antibody–drug conjugate (ADC). (B) The signal-distribution model. This model assumes that following the exposure of ADC, there is a delay in the implementation of the killing signal that is associated with the signal transduction process. (C) The cell-distribution model. This model assumes that following exposure of the ADC, a portion of the growing cells transfers to a series of nongrowing compartments before they are killed eventually.
desirable. In order to accomplish this, either one needs to measure intracellular concentrations of unconju- gated drug in the tumor, which is extremely challeng- ing, or needs to have a PK model that can accurately predict intracellular concentrations of unconjugated drug in the tumor. For the latter option, the tumor PK model for ADC discussed earlier (Figure 4) [8,9] can be employed, and combined with a PD model to characterize the efficacy of ADCs. We have developed one such PK–PD model for ADC by combining the systems PK model developed for ADC with a variant
1642 Bioanalysis (2015) 7(13)
of CDM [8,9]. The model uses intracellular concentra- tions of unconjugated drug to drive the efficacy. Using brentuximab-vedotin the ability of this model to char- acterize as well as predict the efficacy of ADC has been investigated. The PK–PD model was initially used preclinically to characterize the efficacy of brentux- imab-vedotin in several xenograft models following different dosing regimens. From the preclinical data the model was able to estimate the efficacy parameter for the unconjugated drug in the tumor compartment. Since the PK model employed for developing the pre-
future science group Tumor Cell death Signal
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