To determine the plasma pharmacokinetics of Pazopanib after intake of different doses of PazSol001.To determine the preliminary safety and tolerability profile of PazSol001.
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter will be the concentration of Pazopanib in patient
plasma.
Secondary outcome
The second study parameter will be the preliminary safety assessment of
PazSol001.
Background summary
Pazopanib is an oral drug registered as Votrient® (available as 200mg and 400mg
film coated tablets) by GSK. Votrient® has a low solubility and therefore
suffers from impaired and variable absorption.
The Department of Pharmacy and Pharmacology of the Antoni van Leeuwenhoek -
Netherlands Cancer Institute developed an improved solubility solid oral dosage
form for Pazopanib, PazSol 25 mg capsules. This formulation consists of
Pazopanib Hydrochloride and Soluplus®, a graft polymer that has shown great
potency in increasing the solubility of a range of poorly soluble compounds.
In vitro, this formulation releases 100% of Pazopanib upon transition from the
stomach to the duodenum. Votrient® shows ~1% dissolution upon this same
transition. Therefore, the amount of Pazopanib available for absorption into
the bloodstream is considerably higher for PazSol than for Votrient®.
This increased absorption of Pazopanib could give rise to higher plasma
concentrations for the same amount of administered drug
With the low bioavailability of Votrient®, 10-30%, comes a large inter- and
intrapatient variability. This may be reduced by administering a formulation
that has a higher bioavailability, ideally 100%.
In this study, the pharmacokinetics of the new formulation will be tested and
compared to 800 mg Votrient®.
Different PazSol001 doses will be tested to examine if the formulation indeed
increases the bioavailability of Pazopanib as predicted, and secondly to select
the dose to reach the same drug exposure as with 800 mg Votrient®. Animal
studies are not deemed feasible since limited animal (reference) PK data is
available and animal PK may differ significantly from human PK. Translation and
comparison may therefore not be fruitful.
It is expected that a dose of PazSol001 will be found that provides a similar
exposure as 800 mg Votrient® with less Pazopanib load. Extending this
expectation to variability in bioavailability, a higher and less variable
solubility may result in a less variable bioavailability as well, which would
be a major improvement.
If this is the case, the PazSol001 formulation will be taken into further
development. A large scale production line will be designed, set up and
validated. Furthermore, a larger patient study (phase 1) will be proposed with
a direct in vivo comparison between 800 mg Votrient® and the predetermined
PazSol001 dose to show bioequivalence.
Stretching into the future, the patent on Votrient® will expire in 2023 and its
exclusivity in 2019. If and when Pazopanib is still standard care for cancer
patients by then, the new formulation might provide a safer, more efficient and
even a more cost-effective treatment option.
Study objective
To determine the plasma pharmacokinetics of Pazopanib after intake of different
doses of PazSol001.
To determine the preliminary safety and tolerability profile of PazSol001.
Study design
This is a single center, open-label, pharmacological pilot proof of concept
study in which the PK profile of a new oral formulation of Pazopanib,
PazSol001, will be determined and compared to the PK profile of Votrient® 800
mg od. Patients will be hospitalized during 24 hours. On the first day they
will receive one dose PazSol001 (a multiple of capsules of 25 mg) at
approximately 9.00 a.m. After intake of PazSol001 blood samples will be
sequentially collected for bioanalysis for the period of 24 hours.
The PK will be compared to the PK of Votrient 800 mg od. A dose evaluation
committee will determine whether and how the dose will be adjusted for a
possible next cohort. The study will continue until all 12 participants have
finished the study or when 6 participants have taken part in the cohort of
which the results yield an equivalent-to-Votrient exposure.
Study burden and risks
The potential issues of concern for the use of Pazopanib in this study are not
different from those in the registered therapy of patients with Votrient®. We
therefore refer to the Summary of Product Characteristics (SPC) of Votrient®
The potential issues of concern for the improved absorption of Pazopanib are
mainly linked to a possible higher Pazopanib plasma level and the possible
toxicity this may bring with it. To adress this issue, the study is designed to
start with a relatively low dose of Pazopanib (100 mg). Even if all the
Pazopanib is absorbed from this dose, the plasma levels will still be below the
plasma levels of a Votrient® 800 mg dose of which 20% is absorbed (160 mg).
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
1. Locally advanced or metastatic cancer;
2. Age >= 18 years;
3. Able and willing to give written informed consent;
4. WHO performance status of 0, 1 or 2;
5. Able and willing to undergo blood sampling for PK analysis;
6. Minimal acceptable safety laboratory values
a. ANC of >= 1.5 x 109 /L
b. Platelet count of >= 100 x 109 /L
c. Hepatic function as defined by serum bilirubin <= 1.5 x ULN, ALAT and ASAT <= 2.5 x ULN
d. Renal function as defined by serum creatinine <= 1.5 x ULN or creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula).
7. Negative pregnancy test (urine/serum) for female patients with childbearing potential;
8. Able and willing to swallow oral medication;
Exclusion criteria
1. Any treatment with investigational drugs within 30 days prior to receiving the investigational treatment;
2. Any treatment with inhibitors of CYP3A4 (e.g. boceprevir, claritromycine, erytromycine, indinavir, itraconazol, ketoconazol, ritonavir and voriconazol), inhibitors of Pgp (e.g. ciclosporine, kinidine and verapamil), inhibitors of BCRP (e.g. lapatinib), inductors of CYP3A4, Pgp or BCRP or stomach pH increasing drugs;
3. Patients who have had previous treatment with Votrient®, less than 1 week ago;
4. Woman who are pregnant or breast feeding;
5. Patients suffering from any known disease or dysfunction that might influence the dissolution and/or absorption of Pazopanib (e.g. dyspepsia, inflammatory bowel disease).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001105-16-NL |
| CCMO | NL57191.031.16 |