Microdosing as a tool to individualize docetaxel dosing: development of a limited sampling model

Docetaxel is a widely used chemotherapeutic agent accros a variety of tumor
types, including breast-, lung- and non-small cell lungcancer. Although its
dosing is individualized on body surface area (BSE), variability in docetaxel
exposure explains docetaxel variability in toxicity. Docetaxel is mainly
metabolized by the cytochrome P450 isoenzyme (CYP3A). In cancer patients CYP3A
activity may vary a 4-fold. Previous studies showed that a microdose of
midazolam -- like docetaxel a substrate for CYP3A - can reliably predict the
pharmacokinetics of midazolam in therapeutic dose. Therefore, clearance of a
microdose docetaxel might be a good predictor for clearance, and thus exposure
of therpeutic dose docetaxel. The relationship may guide future docetaxel
dosing individualization studies based on CYP3A phenotyping to optimize
treatment and reduce unwanted toxicity.

The primary objective of this study is to establish the relationship between
microdose and therapeutic dose docetaxel pharmacokinetics. Our secondary
objective is to develop a limited sampling model of microdose docetaxel
pharmacokinetics to predict therapeutic dose docetaxel pharmacokinetics.

Observational, prospective cohort study

All patiënts will be administered a single intraveneous microdose(1000
microgram) docetaxel, before regular treatment with the therapeutic dosce.
After the microdose and therapeutic dose blood samples will be collected for
determination of their pharmacokinetics.

The nature and extent of the burden associated with participation are
considered to be minimal, since the only exrta interventions outside of routine
clinical care are administration of midazolam and collection of blood samples.
There is no individual benefit to be expected from participation.