Abstract
Anticancer drugs are valuable assets in the treatment of cancer. However, before a new drug is admitted to the market and available for patients, it has to survive a lengthy path of pre-clinical and clinical studies to demonstrate its efficacy and safety. Critical information required to understand the clinical behaviour
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of a drug is its disposition: the absorption, distribution, metabolism and excretion. This thesis focuses on the ultimate clinical study in which these drug characteristics can be determined: the mass balance study. In a typical mass balance study in oncology, a drug is mixed with a radiolabelled isotope and administered to a small group of patients. After administration, blood samples and excreta are collected and analysed for total radioactivity (unchanged drug plus metabolites), for unchanged drug and for unknown metabolites. The gathered data is used to determine the pharmacokinetic parameters of the drug and to identify the metabolites and major biotransfomation pathways.
After an introductory review outlining the bioanalytical aspects of mass balance studies, this thesis describes the results of these studies for the anticancer agents bendamustine, eribulin, lenvatinib and dovitinib. To support the mass balance studies, quantitative analysis methods needed to be developed for the agents bendamustine, eribulin and lenvatinib. Using liquid chromatography tandem mass spectrometry (LC-MS/MS), assays were established and validated to quantify bendamustine and three metabolites in plasma and urine, eribulin in plasma, urine, whole blood and faeces, lenvatinib in whole blood and lenvatinib and four metabolites in plasma, urine, and faeces.
Four to six patients with advanced cancer were enrolled in the mass balance studies and these patients received a single 14C-radiolabelled dose of the agent under investigation, which was followed by collection of excreta and blood samples. In a subsequent study phase, patients could continue receiving treatment with non-labelled drug in their best interest, whereby safety and efficacy was monitored.
The alkylating agent bendamustine was extensively metabolised and rapidly cleared from plasma. Approximately half of the radioactive dose was recovered in urine and a quarter in faeces. Metabolite profiling of urine with high-resolution mass spectrometry revealed 25 bendamustine-related compounds, including products of N-demethylation, hydroxylation, hydrolysis, N-dealkylation, oxidation, cysteine conjugation and various other conjugations. The range of metabolic reactions was similar as previously demonstrated in rats.
The antimitotic drug eribulin was slowly eliminated and primarily excreted unchanged in faeces. Only minor metabolites were detected in plasma, urine and faeces. The oral tyrosine kinase inhibitor lenvatinib was rapidly absorbed and extensively metabolised, with subsequent excretion predominantly in faeces. Dovitinib, also an oral tyrosine kinase inhibitor, was well absorbed, extensively distributed and mainly eliminated by oxidative metabolism followed by excretion, predominantly in faeces.
In conclusion, quantitative bioanalytical methods were developed and successfully applied in mass balance studies, to extensively investigate their pharmacokinetics. This thesis demonstrates the value of mass balance studies and provides a better understanding of the disposition of four anticancer drugs, thereby contributing to the development of these drugs.
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