(540.3) A novel integrated pharmacokinetic-pharmacodynamic model for the determination of in vivo synergism of combination therapy

Poster Board Number: B128

Young Hee Choi (Dongguk University-Seoul, UC Davis School of Medicine), Mei-Juan Tu (UC Davis School of Medicine), Aiming Yu (UC Davis School of Medicine)

Establishment of pharmacokinetic-pharmacodynamic (PK-PD) relationship is critical for dose optimization during drug development and clinical therapy. While combination therapy is common, especially in oncology, conventional PK-PD models do not recognize quantitative contributions from individual drugs. Rather, only one “interaction factor” is used in those models and arbitrarily assigned to a specific drug. Meanwhile, the interaction factor is overstretched to define pharmacologic synergism in vivo. In this study, we developed a novel PK-PD model for combination therapy by considering apparent contributions from individual drugs or mutual interactions. Doxorubicin (Dox) and sorafenib (Sor) were used as model drugs whose PK data were obtained in mice and fit to two-compartment models. Xenograft tumor growth showed biphasic features in mice and anticancer drug responses were described by three-compartment transit models. This PK-PD model revealed that Sor (contribution factor = 1.62) had much greater influence than co-administered Dox (0.644) on overall tumor growth inhibition, which explains the mysterious clinical findings on a remarkable benefit for cancer patients when Sor is added to Dox treatment, whereas none when Dox is added to Sor therapy. Furthermore, we incorporated the combination index method into this PK-PD model to critically determine in vivo synergism which, however, cannot be accurately defined by interaction factor method. Additionally, this new PK-PD model readily predicts optimal dosage combinations to achieve greater extents of tumor growth inhibition that are consistent with stronger synergy. These results support the utilities of this new PK-PD model and reiterate the application of valid method for the evaluation of in vivo synergism.

This study was supported by grants R01CA225958 and R01GM133888 from the National Institutes of Health.