Pharmacometric approaches to improve theranostics

Abstract

Radiopharmaceuticals are considered highly valuable for diagnosis and therapy of several types of cancers. Radiopharmaceuticals currently used for neuroendocrine tumors (NETs) and prostate cancer are applied in a theranostic approach. This approach comprises the use of comparable tumor targeted radiopharmaceuticals for both diagnosis and therapy, which is achieved by using peptides labeled with different radionuclides that determine whether the radiopharmaceutical is used for therapeutic or diagnostic purposes. This theranostic aspect of radionuclide therapies advocates for applying precision medicine to improve these therapies, which can be accomplished by using pharmacometric approaches. Pharmacometric approaches are a proven and often applied mathematical tool to study the absorption, distribution, metabolism and excretion of drugs. Such pharmacokinetic (PK) modelling and simulation applications are regularly used for development and clinical research of nonradioactive drugs. Although these approaches also have a potential benefit in improving the evolving research regarding radiopharmaceuticals, its use for radiopharmaceuticals is surprisingly limited. To evolve theranostic agents towards patient-centered precision medicine, PK modelling and simulation approaches should be regularly applied to radiopharmaceuticals similar to nonradioactive drugs. By applying these pharmacometric approaches, this thesis focused on gaining a better understanding of PK of several theranostic agents.

Part I introduced two PK modelling approaches, namely population PK models and physiologically based pharmacokinetic (PBPK) models. The relevance of PK modelling for radiopharmaceuticals and its great potential for the nearby future was underlined, which was the central thread of this thesis. Part II focused on improving the application of theranostic agents in patients with advanced stage NETs (Gallium-68 (68Ga) labeled to DOTATATE or HA-DOTATATE for diagnosis and Lutetium-177 (177Lu) labeled to HA-DOTATATE for therapy). In five chapters, we identified factors that impact biodistribution of several compounds, assessed the effect of different peptide doses on tumor and organ accumulation (to reveal potential receptor saturation), predicted therapeutic uptake based on single time point pre-treatment imaging and quantified a cycle effect (i.e. uptake in tumors reduced over treatment cycles) for [177Lu]Lu-HA-DOTATATE . In Part III, all chapters contributed to improve the use of theranostic agents for prostate cancer (68Ga labeled to the prostate specific membrane antigen (PSMA) ligand for diagnostic imaging and 177Lu labeled to PSMA for therapy). In four chapters, we assessed the effect of peptide amount on tumor accumulation, investigated the effect of folates on [68Ga]Ga-PSMA-11 accumulation, described population PK and identified relatively minor inter-individual variability for [177Lu]Lu-PSMA-617 and developed a PK/PD model for [177Lu]Lu-PSMA-I&T to describe individual biochemical prostate-specific antigen response after therapy.

In summary, this thesis described the use of pharmacometric approaches and data analyses to optimize theranostic applications for NETs and prostate cancer. Nuclear imaging data were successfully used to develop and evaluate different PK models of several radiopharmaceuticals. In addition, this thesis pointed out that pharmacometric approaches are a useful approach to answer many remaining questions in nuclear medicine research. Therefore, the time is ripe to start applying pharmacometric approaches to radiopharmaceuticals on a regular basis, similar to its use in drug development and clinical research of nonradioactive drugs.