Therapeutic Drug Monitoring to Individualize the Dosing of pazopanib: a Randomized Pharmacokinetic Feasibility Study

In the recent years, nine tyrosine kinase inhibitors (TKIs) and two m-TOR
inhibitors have been approved for cancer treatment and numerous are under
investigation. These targeted anticancer therapies are generally considered to
be less toxic than conventional chemotherapy since they specifically inhibit
cellular processes that are deregulated in various types of tumor cells.
However, dose interruptions or reductions appears to be necessary in a large
number (20 * 50%) of patients treated with these drugs. Additionally, recent
publications indicate that efficacy might be related to TKI exposure. Since
TKIs and m-TOR inhibitors show a large interpatient variability (35 * 60%) the
fixed dose administered will result in very different exposure levels between
individuals resulting in supratherapeutic or subtherapeutic exposure levels and
consequently in over- or undertreatment. Dose individualization based on the
measured drug concentration could theoretically result in less toxicity and
more efficacy. However before the effect of dose individualization on the
clinical outcome can be studied the effect of pharmacokinetic guided
individualization on the interpatient variability should first be studied.
Since, if we are incapable of inducing a more predictable and stable drug
exposure (reduced interpatient variability) by introduction of PK guidance *
titration of the drug based on PK guidance will never lead to the predefined
exposure level / trough level.

Primary objective
To evaluate the effect of PK-guided individualized dosing of pazopanib on the
interindividual variability in drug exposure.

Secondary objective
- To determine the correlation between pazopanib trough and exposure levels
- To determine the accuracy of the exposure levels (e.g. the deviation between
the mean AUC at fixed dose and after dose adjustment) after the introduction of
PK guided dosing
- To determine the effect of pazopanib exposure on the systolic and diastolic
blood pressure
- To determine the effect of dose individualization on the frequency of the
scored adverse events (CTCAE v4.0)
- To investigate the feasibility and accuracy of quantifying pazopanib
concentrations with dried blood spot sampling.

The study is a randomized, multicenter, open label, cross-over design phase I
study.
Patients are initially randomized to either the fixed dose treatment arm or the
PK-guided treatment arm. The target exposure (AUC) of 805 *g*hr/mL is derived
from the mean exposure level measured in 29 patient treated with a single dose
of pazopanib 800 mg (AUC0-t after a single dose is equal to AUC0-24 at
steady-state)1. All patients will start with the standard dose:
- once daily 800 mg pazopanib, 1hr before or 2hr after food consumption
At day 14, blood samples are collected at 0, 1, 2, 3, 4, 6, 8, 10 and 24 hours
after pazopanib from patients in both treatment arms and measured within 3
business days by LC-MS/MS. In the PK-guided treatment part the therapy will be
continued with an adjusted dose based on the deviation between the target (805
*g*hr/mL) and measured exposure (table I)1. Patients in the fixed dose
treatment arm will continue with the same dose as started with.
Fourteen days after the dose adjustment the exposure to the drug will be
measured again in both treatment arms.
At day 28, the second PK-observation day, patients will switch between the
treatment arms. The dose of the patients in the fixed arm will be adjusted
based on the deviation between the target and measured exposure. The patients
in the PK-guided arm will return to the standard dose.
At the third PK-observation day, day 42, the exposure to the drug will be
measured in both treatment arms (figure I).

The pazopanib plasma concentration will be measured within 3 business days
after the last sample collected by LC-MS/MS. The treating physician will call
the patient to communicate the adjusted dose and explain details regarding the
adjusted dose (e.g. number of tablets, possible side effects that require
earlier contact).

Systolic and diastolic blood pressure will be measured at four different time
points over a time frame of three hours at baseline and at day 7, 14, 28 and 42
after initiating pazopanib therapy.

All patients will return to the standard treatment intensity and will remain on
treatment until they do no longer have clinical benefit from treatment,
progressive disease according to RECIST V1.1 or if adverse events lead to
patient withdrawal.

Patients with an elevated dose who develop adverse events and theoretically
require a dose reduction according to the section *Dose Modification Algorithms
for Potential Treatment-Related Adverse Events* will be evaluated for earlier
PK assessment (measurement of AUC0-24hr) after which they can return to the
standard dose of 800 mg pazopanib OD. If earlier PK assessment is not
legitimate they will be withdrawn from the study and replaced by a new eligible
patient.
All other patient who develop adverse events and theoretically require a dose
reduction according to the section *Dose Modification Algorithms for Potential
Treatment-Related Adverse Events* will be evaluated for earlier PK assessment;
thereafter they will be withdrawn from the study and replaced by a new eligible
patient.

PK guided dose adjustments based on a dosing algorithm

Patients are admitted to the hospital for 3 days in a six week period
Blood sampels are withdrawn - total of 27 sampels of 5mL

Benefit
Patients are treated with a active compound that might result in tumor response