Pharmacokinetic-Pharmacodynamic Modelling & Simulation for Anticancer Drugs with Complex Absorption Characteristics

Abstract

Cancer is still one of the leading causes of death in the world. In recent years, targeted anticancer agents have shown to be a major breakthrough in the battle against cancer. These targeted anticancer agents, mostly administered orally, specifically target molecular defects of tumour cells resulting in tumour shrinkage. On the other hand, classical cytotoxic anticancer agents are still widely used and the oral administration of these agents has proved to be a safe alternative for intravenous administration. Many orally administered anticancer agents show complex absorption characteristics which may lead to insufficient drug exposure or highly variable pharmacokinetics (PK), which limit their clinical use. In order to understand the PK and the PK-pharmacodynamic (PD) relationships of these drugs to further support their clinical use, this thesis applied PK-PD modelling and simulation in the studies of the anticancer drugs with complex absorption characteristics. Firstly, the PK and PK-PD relationships of anticancer tyrosine kinase inhibitors (TKIs), a group of targeted agents, were systematically reviewed. It has been shown that these drugs exhibit a high variability in PK. Then, the PK of two widely used TKIs, sunitinib and pazopanib, were characterised by PK modelling and simulation. It was found that the pre-systemic metabolism of sunitinib is important and cannot be neglected. The PK model of pazopanib suggested that (i) pazopanib absorption consists of a fast and a slow phase; (ii) the bioavailability of pazopanib is saturable; and (iii) pazopanib exposure decreases in the first four weeks of treatment. In addition, the thesis studied the PK and PK-PD relationships of two drugs of the taxanes from the group of classical cytotoxic anticancer agents, docetaxel and paclitaxel, with co-administration of metabolic enzyme inhibitor ritonavir. PK modelling of the combination treatment of oral taxanes and ritonavir succeeded in quantifying the effects of ritonavir on oral taxane exposure and supporting the clinical development of oral taxanes by the comparison of different oral formulations on absorption rate, bioavailability, and variability, etc. Further, a PK-PD model of the tumour growth inhibition of docetaxel-ritonavir treatment in mice was established. It showed that ritonavir not only boosted the intratumoural exposure to docetaxel but also had a small contribution to the anticancer effect. Besides, a PK-toxicodynamic model was established to relate the exposure to oral docetaxel to the probability of dose-limiting toxicity in patients. This model will further support the dose selection for future clinical trials. Concluding, this thesis showed the application of the PK and PK-PD modelling and simulation of oral anticancer drugs to optimise their use in the clinic. The developed models can be used to optimise dosing strategies either on the population level (e.g. improved dosing regimens, development of optimal combination strategies, evaluation of improved formulations) or on the individual level (e.g. by application of therapeutic drug monitoring or by detection of important covariates). Ultimately, these optimised dosing regimens need validation in clinical trials, which in turn may yield important data which can be used to refine the developed models.