Absolute bioavailability trial of oral imatinib (Glivec®) using a stable isotope labeled intravenous imatinib microdose.

Absolute bioavailability (ABA) is a measurement of the rate and extent to which
the active ingredient or active moiety of a drug is absorbed, reaches the
systemic circulation and becomes available at the site of action. ABA
assessment is an important component of new drug development. ABA data in
humans is increasingly requested by the EMA and FDA for new chemical entities.

Small molecular tyrosine kinase inhibitors (smTKIs) are generally characterized
by a poor oral, and thus variable, bioavailability. This results in significant
variation in plasma levels and exposure. For many smTKIs, the human oral
bioavailability is unknown or inaccessible in the public domain due to several
reasons and if published, values are generally low and the exposure is
variable. Imatinib (Glivec®, Novartis) is an exception to this case with almost
complete bioavailability in humans after oral dosing.

Glivec® bioavailability was tested in twelve healthy volunteers using a
traditional three-period randomized crossover trial approach, where patients
were assigned to 100 mg of imatinib as a 60-minute IV infusion, 400 mg of
imatinib as a capsule, or 400 mg of imatinib as an oral solution in different
sequences. The absolute bioavailability of oral imatinib either as a solution
or in capsule form was found to be higher than 97%. (1)

Absolute oral bioavailability is ideally studied using a microtracer approach.
This can be done by administering a therapeutic dose of the drug via the non-IV
route, after which a microtracer (either radiolabelled drug or stable isotope
labeled (SIL) drug is given via the IV route at 1/100th of therapeutic dose or
less than 100 µg at the expected Tmax. This approach has several advantages
over the traditional crossover study design.

First, since the dose of the microtracer is very low, supportive IV toxicology
studies are not required. Second, formulation development work is also limited.
Even very insoluble compounds can be easily formulated with physiological
concentrations of saline, glucose, or co-solvent at such a low dose. Third, the
IV microtracer is administered at the peak concentration of the non-IV route at
steady state, at which time the body is already behaving in the therapeutic
dosing range, therefore, the possibility of non-equivalent kinetics that might
otherwise occur between separate dosing occasions is virtually limited. And
fourth, a microtracer study with a single dosing period shortens the study
duration and eliminates interoccasion variability present in the crossover
study design.

With the recent advancement of ultrasensitive liquid chromatography with tandem
mass spectrometry (LC-MS/MS) technologies, it is now possible to accurately
measure drug concentrations in plasma following an IV administration of a
stable isotope labeled microtracer using LC-MS/MS. Therefore, it is no longer
required to use a radiolabeled drug (often 14C) as the microtracer. This can
save time and money, as accelerator mass spectrometry (AMS), which is the
analysing technique for 14C-labeled microdoses, is labour- and time-intensive
and more costly than LC-MS/MS.

The aim of this proof of concept study is to determine the ABA of imatinib
using a SIL-microtracer trial design. Imatinib is chosen as a model compound
because ABA trial results using a cross-over trial design are already
available. (1) The results obtained from this new proof of concept study can be
compared to the results obtained using the traditional cross-over trial design.
When the results are comparable, this study provides proof that microtracer ABA
trials are feasible in our institute, making it possible to reduce patient
burden and saving costs and time in future trials where the ABA of oral
anticancer agents needs to be investigated.

To determine the absolute bioavailability of imatinib (Glivec®) at steady state
after concomitant administration of a single 100 µg microdose of imatinib-d8

This is a single center, open-label, single dose, absolute bioavailability
study in which the absolute bioavailability of imatinib (Glivec®) will be
determined at steady state by concomitant administration of an IV microdose of
stable isotope labeled imatinib-d8. Patients will be hospitalized during 24
hours. After intake of Glivec® (at around 08:30 a.m.) blood samples will be
sequentially collected for bioanalysis for the period of 24 hours. On the first
day they will receive one intravenous dose of 100 µg imatinib-d8 at
approximately 11.00 a.m. An additional 48 hour post-dose sample will be
collected in an outpatient setting.

Injection of a 100 microgram imatinib-d8 microdose

Burden:
• Placement of a Venflon catheter;
• Administration of the IV microdose imatinib-d8;
• 12 x 4 mL blood sample collections;
• Hospital visit lasting at least 24 hours;
• 1 follow-up visit;

As microdosages are considered non-therapeutic and non-toxic, no risk is
expected to be associated with administration of the imatinib-d8 microdose.