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A Novel Integrated Pharmacokinetic-Pharmacodynamic Model to Evaluate Combination Therapy and Determine In Vivo Synergism by Young Hee Choi; Chao Zhang; Zhenzhen Liu; Mei-Juan Tu; Ai-Xi Yu; Ai-Ming Yu is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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Understanding pharmacokinetic (PK)-pharmacodynamic (PD) relationships is essential in translational research. Existing PK-PD models for combination therapy lack consideration of quantitative contributions from individual drugs, whereas interaction factor is always assigned arbitrarily to one drug and overstretched for the determination of __in vivo__ pharmacologic synergism. Herein, we report a novel generic PK-PD model for combination therapy by considering apparent contributions from individual drugs coadministered. Doxorubicin (Dox) and sorafenib (Sor) were used as model drugs whose PK data were obtained in mice and fit to two-compartment model. Xenograft tumor growth was biphasic in mice, and PD responses were described by three-compartment transit models. This PK-PD model revealed that Sor (contribution factor = 1.62) had much greater influence on overall tumor-growth inhibition than coadministered Dox (contribution factor = 0.644), which explains the mysterious clinical findings on remarkable benefits for patients with cancer when adding Sor to Dox treatment, whereas there were none when adding Dox to Sor therapy. Furthermore, the combination index method was integrated into

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Author

Young Hee Choi; Chao Zhang; Zhenzhen Liu; Mei-Juan Tu; Ai-Xi Yu; Ai-Ming Yu

Publisher

American Society for Pharmacology & Experimental Therapeutics (ASPET)

Published

2021

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)