On 22 January, pharmacologist Merel van Nuland will defend
her thesis on the clinical pharmacology of anti-cancer
drugs. Merel did her PhD research at the NKI and will defend
her thesis at Utrecht University.
Variability in drug exposure
The development of new drugs to treat cancer has
increased significantly over the past years. Many of the newly
developed targeted drugs are administered orally, causing an
increased variability in drug levels and exposure compared to
intravenously administered drugs. Variability in drug exposure may
have consequences for treatment efficacy and toxicity. Therefore, a
better understanding of the pharmacology - the
interaction between drugs and physiological processes - may
further optimize treatment and improve drug safety.
Therapeutic drug monitoring
In this thesis, the clinical pharmacology of anti-cancer
drugs are described, with a focus on bioanalysis, therapeutic drug
monitoring (TDM) and microdosing. Therapeutic drug monitoring, or
TDM, is the clinical practice of measuring drug concentrations in
biological matrix to be used for individualization of drug dosing,
in other words patient-tailored dosing. TDM was shown to optimize
treatment for abiraterone acetate, while there was no evidence
found to support TDM of enzalutamide.
Microdose trials are exploratory investigational drug trials in
which 1/100th of the therapeutic dose, with a maximum of 100 μg, is
administered to human subjects. The question raised is if microdose
pharmacokinetics - what the body does to a drug
- are indicative for pharmacokinetics at therapeutic dose. In
a pilot study, we have shown that the volume of distribution and
elimination pattern of gemcitabine differs after administration of
microdose compared to a therapeutic dose.