Text

theses

In 2016, it was estimated that more than 15.5 million cancer survivors were living in the US, and this number will increase to more than 20 million by 2026. Highly effective treatments have been developed, and the increase in survival demands more attention to patient’s quality of life and management of adverse effects. Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse effect of various cancer therapies, such as paclitaxel and cisplatin. CIPN is one of the most challenging pain conditions with poor response to pharmacotherapy; therefore, discontinuation of chemotherapy or dose reduction often remains the only clinical solution.
The thesis focused on using quantitative approach for improving our understanding of the relationships between tissue distribution of the chemotherapeutic agents and CIPN development. In an introductory Chapter 1, an overview of the chemotherapeutics, CIPN, formulations, and modeling approaches is presented. In Chapter 2, a physiologically-based pharmacokinetic (PBPK) model was developed to characterize the whole-body disposition of paclitaxel following administration of a commercially available formulation (Taxol®). Pharmacokinetic data of paclitaxel in mice from multiple publications was collected and used for model development. Interspecies scaling approaches were incorporated in the model and provided reasonable prediction of tissue disposition of paclitaxel in rats and plasma pharmacokinetics in humans. In Chapter 3, a nanoparticle formulation of paclitaxel was developed. The neurotoxicity development in rats was significantly reduced after administration of the PEGylated liposomal paclitaxel compared to Taxol®. The formulation has also significantly altered paclitaxel disposition into tissues. In Chapter 4, a quantitative relationship between the dose, plasma pharmacokinetics, and paclitaxel-induced peripheral neurotoxicity was established by evaluating the paw withdrawal threshold to mechanical stimuli after intravenous administration of Taxol® to rats using experimental data and published literature. Indirect response models adequately described the pharmacokinetic-pharmacodynamic relationship. In Chapter 5, a PBPK model of cisplatin (another neurotoxic compound) was developed based on multiple published data sets from preclinical species. The model included the uncommon metabolism and binding pattern of cisplatin, and an interspecies scaling approach based on protein turnover rate was developed. The model successfully predicted cisplatin pharmacokinetics in humans. Collectively, the studies provided important insights into quantitative relationships for neurotoxic chemotherapeutics. Translational PBPK and PK-PD modeling approaches can be further utilized for optimization of therapy with neurotoxic chemotherapeutics.

ETD_9383

Ph.D.

Includes bibliographical references

by Xiaowei Zang

doi:10.7282/t3-qagq-zr63

ETD doctoral

The author owns the copyright to this work.