Cyclin-dependent kinase inhibitors in cancer: bioanalysis and pharmacokinetics

Abstract

Cancer remains a leading global health problem with expected increases in incidence and mortality for the coming years. New cancer therapies have focused on targeted anticancer drugs, which have demonstrated to have higher efficacy and reduced toxicity compared to traditional cytotoxic drugs. The cyclin-dependent kinases (CDKs) have been regarded as promising targets for cancer, since they can control critical checkpoints in the cell cycle when activated by cyclins. To date, three CDK inhibitors selective for CDK4 and CDK6 have been approved: palbociclib, ribociclib and abemaciclib. These drugs are currently used for the treatment of metastatic or advanced breast cancer, and their efficacy for other malignancies is being investigated. In addition, clinical studies of many other CDK inhibitors with different CDK subclass specificity are ongoing.

This thesis addresses several pharmacological aspects of the CDK inhibitors, from bioanalysis (Part I) to preclinical (Part II) and clinical pharmacokinetics (Part III), focusing mainly on the approved CDK4/6 inhibitors: abemaciclib, palbociclib and ribociclib. However, it also examines milciclib, a promising CDK2 inhibitor that is currently clinically investigated for treatment of some malignancies.

As reliable bioanalytical methods are pivotal for an appropriate conduction and performance of preclinical and clinical studies of drugs, part I of this thesis focusses on the development and validation of bioanalytical methods for the quantitative analysis of CDK inhibitors. Full method validation was performed according to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The bioanalytical methods provided in part I were used to support the pre-clinical investigations conducted in part II of this thesis.

Drug transporters and drug-metabolizing enzymes can influence the disposition of substrate drugs with clinically relevant (pharmacodynamic) consequences. Thus, using in vitro and various genetically modified mouse models, part II of this thesis investigates the role of efflux (ABCB1 and ABCG2) and uptake transporters (OATP1) and cytochrome P450 3A (CYP3A) enzymes in the pharmacokinetics and tissue distribution of CDK inhibitors.

Finally, in Part III, the clinical pharmacokinetics and pharmacodynamics of the approved CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) is reviewed. Here, the pharmacokinetics of these drugs in normal and specific populations is described, as well as some extrinsic factors that affect it, including the food effect and the interaction with other drugs. Similarities among the pharmacokinetics of these drugs included their extensive metabolism by CYP3A4, their brain penetration limited by efflux transporters, and their large interindividual variability in exposure. Furthermore, this chapter highlights the exposure–response and exposure–toxicity relationships.

In conclusion, the insights into different aspects of the CDK inhibitors provided in this thesis may be useful to optimize the clinical use of abemaciclib, palbociclib and ribociclib. Additionally, this can potentially contribute to the further development of these drugs and milciclib. Ultimately, this information hopefully could lead to CDK treatments with improved efficacy and safety.