Real-world exploratory evaluation of the potential drug-drug interaction between anticancer small molecule inhibitors and direct oral anticoagulants in patients with solid tumours, and exploration of the role of therapeutic drug monitoring

Patients with a solid tumour who are treated with oral anticancer small
molecule inhibitors (SMIs) and simultaneously use a direct oral anticoagulant
(DOAC) potentially hav ean increased risk on thromboembolic complications and
bleeding events due to interfering drug-drug interactions. As some SMIs
influence CYP3A4 and/or p-glycoprotein (p-gp) for which DOACs are substrate,
concurrent use of SMIs and DOACs may increase or decrease DOAC exposure.
However, data on the clinical relevance and subsequent safety consequences of
these potential drug-drug interactions (pDDI) is lacking.

Primary Objective: to explore the effect of SMIs on the pharmacokinetics of
DOACs in patients with solid tumours who receive a DOAC and SMI concurrently.

Secondary Objective(s):
- To determine the percentage of patients with DOAC peak and trough
concentrations within and outside the expected ranges (table 1 - 4).
- To determine the percentage of patients in whom DOAC treatment during routine
care is modified by the treating physician, based on DOAC plasma concentration
measurements, obtained during the study period.
- To evaluate steady-state SMI trough concentration during concurrent DOAC
treatment.
- To exploratively evaluate the effect of SMIs on the pharmacokinetics of DOACs.
- To evaluate the frequency of thrombo-embolic and bleeding events in this
population, using both an SMI and a DOAC.
-
Additional exploratory objectives
- To explore the feasibility of pharmacokinetic guided dosing of DOACs (when
used in combination with potentially interacting co-medication).
- To explore if the extent of drug interaction between SMI and DOAC may be SMI
exposure dependent.
- To evaluate the effect of SMIs on the functional activity of DOACs measured
by in vitro thrombin generation.

In this prospective, multicentre, real-life, basket study, patients with solid
tumours who are treated with or start treatment with an SMI in combination with
a DOAC will be included. Trough and peak DOAC plasma concentration in steady
state will be measured, before and after SMI initiation (or vice versa), to
study the pDDI between SMIs and DOACs. Additionally, SMI trough plasma
concentrations will be measured, when steady-state is reached. Results of the
DOAC plasma concentration analysis will be reported to the treating physician
after which patients continue with regular care. If considered necessary by the
treating physician to change DOAC treatment (i.e. DOAC dose adjustment or
switch to another DOAC) based on the reported DOAC plasma concentrations and
regular care advice from a hospital pharmacist and/or internist-vascular
medicine, the patient may re-enter the protocol for additional DOAC plasma
concentration analysis. All patients will be followed to evaluate the safety
and efficacy of their DOAC therapy by evaluating the occurrence of any
thromboembolic or bleeding events.

Patients participating will be asked to give blood samples for trough and peak
concentration measurements and thrombin generation analysis. This can be done
using a venepuncture and will be combined with regular outpatient clinic
appointments as much as possible. Patients will receive or continue treatment
with an SMI (and, if necessary, supportive) treatment as planned and therefore
will not be at significantly increased risk. Furthermore, DOAC treatment will
be initiated as per regular care, but may be optimized, since therapeutic drug
monitoring (TDM) has the potential to facilitate more effective use of DOACs in
individual patients using potentially interacting SMIs. Therefore, the risk of
study participation is negligible. Additionally, patients are asked to keep a
medication diary (only group 1) between the first and second day of drug plasma
concentration measurements or until the day of the last drug plasma
concentration measurements to monitor treatment adherence which is not
burdensome or time-consuming for patients.