A PK-PD Modeling and Simulation Based Strategy for Clinical Translation of
Antibody-Drug Conjugates: A case study with T-DM1
Aman Singh, PhD
PhD Candidate
Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY
April 19, 2017, 12:00 pm to 1:00 pm EDT
Register at http://www.rosaandco.com/webinars/2017/singh
Abstract: Successful clinical translation of Antibody-Drug Conjugates (ADCs)
can be challenging due to complex pharmacokinetics and differences between
preclinical and clinical tumors. In this webinar, we will present application
of a PK-PD based strategy for successful bench to bedside translation of ADCs
using T-DM1 as an example. A mechanistic cellular disposition model was
developed incorporating intracellular ADC degradation and passive diffusion of
unconjugated drug across tumor cells. Specific biomeasures and chemomeasures
reported for T-DM1 in the literature were incorporated in the model of ADC to
characterize in vitro pharmacokinetics of T-DM1 in three HER2+ cell lines. When
the cellular model was integrated with an in vivo tumor disposition model, the
model was able to a priori predict tumor DM1 concentrations in xenograft mice.
Later, our integrated preclinical PK-PD model was used to characterize tumor
growth inhibition (TGI) data in multiple HER2+ mouse models with varying level
of HER2 expression. Clinical pharmacokinetics of T-DM1 was predicted by
allometric scaling of monkey PK parameters. Finally, the predicted human PK,
preclinically estimated efficacy parameters, and clinically observed volume and
growth parameters for breast cancer were combined to develop a translated
clinical PK-PD model capable of performing clinical trial simulations. Our
model simulated PFS rates for HER2 1+ and 3+ populations were comparable to the
rates observed in 3 different clinical trials. The model predicted only a
modest improvement in ORR with an increase in clinically-approved dose of
T-DM1. However, the model suggested that a fractionated dosing regimen (e.g.
front loading) may provide an improvement in the efficacy. In general, the
PK-PD M&S based strategy presented here is capable of a priori predicting the
clinical efficacy and this strategy has now been validated for all clinically
approved ADCs.