Clinical pharmacology of novel anticancer agents: bioanalysis - clinical pharmacokinetics - mass balance studies

Cancer is already among the leading causes of death worldwide and the number of new cases is expected to rise by about 70% over the next two decades. Even though the number of new cases will rise, the survival rates are also increasing due to earlier diagnosis and/or more effective treatment. Better knowledge about the absorption, distribution, metabolism and excretion (pharmacokinetics) of a drug and its possible correlation to treatment outcome and toxicity may contribute to increased efficacy and better tolerance of therapy. This thesis describes the characterization and quantification of the pharmacokinetics of (new) anticancer drugs, which adds new useful information to the large pool of knowledge of quantitative pharmacokinetics in cancer treatment. BioanalysisAssays for the quantification of vemurafenib, dabrafenib, trametinib, cobimetinib, and olaparib in plasma and vemurafenib in dried blood spot (DBS) samples were developed to support clinical pharmacokinetic studies of these targeted therapies. Assays for the quantification of omacetaxine and vosaroxin in plasma and urine were developed to support mass balance studies with these new chemotherapeutic agents. All quantitative bioanalytical assays were based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Clinical pharmacologyThis thesis also describes pharmacokinetics of (new) anticancer drugs using therapeutic drug monitoring and clinical human mass balance studies. Therapeutic drug monitoring enables further investigation of the pharmacokinetics of the drug and its correlation to efficacy and toxicity in daily practice. Clinical mass balance studies are clinical phase I studies, which are performed to increase the knowledge of the pharmacokinetics, and particularly metabolism and excretion, of a drug during clinical development. Clinical pharmacology of targeted therapies To be able to use DBS sampling to determine the vemurafenib plasma concentration the relationship between plasma and DBS concentrations of vemurafenib was established. The results enabled us to collect DBS samples for clinical studies and pharmacokinetic monitoring instead of plasma samples. In a real life cohort of melanoma patients, high inter-patient variability in plasma concentrations was observed. This study also showed that approximately half of the patients were underexposed (mean plasma concentration <42 µg/mL), which indicates the need for pharmacokinetic monitoring during vemurafenib treatment.Mass balance studiesIn this thesis three mass balance studies are described of reversible protein translation inhibitor omacetaxine, quinolone derivative vosaroxin and multiple tyrosine kinase inhibitor lenvatinib. The mass balance study and additional metabolite profiling of omacetaxine showed that omacetaxine has no main excretion route, since omacetaxine-derived compounds were found equally in urine and in feces. Vosaroxin was metabolized into ten metabolites after which it was excreted in urine and, more predominantly, in feces. The last compound that was investigated in a mass balance study was multi-targeted TKI lenvatinib. After oral administration lenvatinib was rapidly absorbed and unchanged lenvatinib was the main compound found in plasma. ConclusionThe results described in this thesis provide a better understanding of the pharmacokinetics of the investigated drugs discussed. In addition the proposed hypotheses may serve as a starting point for further research on pharmacokinetic monitoring and optimization of targeted cancer therapies.