Human mass balance and metabolite profiling studies of the new anticancer agents plitidepsin, lurbinectedin and niraparib

There is a vast increase in the number of newly developed anticancer therapeutics, of which marine-derived anticancer drugs and the poly(ADP-ribose) polymerase (PARP) inhibitors are successful examples. Besides investigating whether the drug and dose given are effective, of course it also needs to be safe. Especially in oncology, drug concentrations found in plasma can often be correlated with therapeutic effect and/or toxicity. The drug itself can cause unwanted side-effects, but occasionally the metabolites formed are responsible for toxicities. As part of the registration procedures, metabolite profiling studies are now mandatory. These studies are typically referred to as radiolabelled mass balance studies and essentially they are the perfect way to investigate pharmacokinetic properties, such as absorption, distribution, metabolism and excretion (ADME). An analytical problem with these studies in terms of metabolite identification and quantification, however, is that reference standards of the metabolites are usually not available. This is often due to unfamiliarity of these compounds at that stage. A mass balance and metabolite profiling study can provide the missing information. A radiolabel incorporated in the drug of investigation can act as a guide to track down and to identify metabolites when the metabolite contains the radiolabel as well. By combining radioactivity measurements with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, ample information on metabolites can be gathered. In addition, high accuracy MS data are indispensable in determining the elemental compositions of metabolites, which, in combination with MS fragmentation patterns, can lead to the irrefutable elucidation of metabolite structures. This thesis describes the methods and results of three mass balance clinical studies in which cancer patients received radioactive plitidepsin, lurbinectedin or niraparib. It describes many (bioanalytical) aspects of these new drugs, ranging from describing the challenges observed in the laboratory, as well as in the clinic, focusing on sample collection and preparation, highlighting the excretion pathways, identifying and quantifying the metabolites formed in vivo by numerous biotransformation reactions and ultimately deciding whether the newly found metabolites should be investigated further. All in all, this thesis outlines a wide variety of aspects of pharmacological studies of anticancer drugs in human subjects. Hopefully, it has contributed further to a better understanding of the pharmacology of these drugs and ultimately to a more efficacious and less toxic application in cancer patients.