Canagliflozin REnal Distribution Intervention Trial (CREDIT); A feasibility study for the use of 18F-canagliflozin to quantify individual differences in target-site exposure in diabetes patients

Recently, a novel class of glucose lowering drugs, the SGLT2 inhibitors, is
approved as second-line therapy in the treatment of DM2. These drugs have shown
to improve glycemic control, slow progression of diabetic kidney disease and
show beneficial effects on cardiovascular end points, in particular reduction
of heart failure (Neal et al., 2017). However, the response to SGLT2 inhibitors
in markers of kidney function (albuminuria, eGFR) varies between individuals
such that approximately 20% of patients does not show improvement in glycemic
control (Petrykiv, de Zeeuw, et al., 2017; Petrykiv, Laverman, et al., 2017).
The underlying mechanisms of drug response variability for SGLT2 inhibitors,
but also other drugs used for the prevention and treatment of DKD, are unknown.
Understanding these mechanisms should lead to more effective treatment
strategies for these high-risk individuals. The ultimate aim of this study is
to determine the underlying mechanisms and determinants of the variability in
drug response. This will lead to the identification of previously unknown
factors that determine therapy response and provide the potential to improve
the treatment of microvascular complications of type 2 diabetes in the future.
We hypothesize that the underlying mechanisms of the varying response in
multiple parameters within an individual can be attributed to variability in
the causal path between drug administration, drug tissue distribution, and
tissue receptor interaction.
To test this hypothesis we have synthesized an 18F PET radiotracer of the SGLT2
inhibitor canagliflozin, retaining the original molecular structure and
therefore pharmacodynamic properties are not changed. This drug class was
selected for several reasons. First, it represents an established blood glucose
lowering drug in the treatment of type 2 diabetes and given the positive
effects on cardiovascular outcomes and good tolerability it is likely that in
the near future SGLT2 inhibitors will form the guideline recommended therapy
for patients that do not respond well on diet and/or metformin. The advantage
of canagliflozin over other SGLT2 inhibitors is that it is particular suitable
for PET imaging since it carries an F-atom which can be replaced for 18F
without changing the molecular structure of the compound and thus retains its
pharmacodynamics properties.
In this clinical feasibility study we will assess 18F-canagliflozin
pharmacokinetic characteristics and determine specific receptor binding,
receptor occupancy and optimal scanning time in 9 selected subjects with type 2
diabetes.

The main objectives are:
• To assess canagliflozin target (i.e. receptor) specific binding in vivo
• To assess receptor occupancy of canagliflozin in vivo
• To determine optimal scanning time in vivo

To explore the relationship between canagliflozin disposition and changes in
the following parameters: (estimated) Glomerular Filtration Rate, plasma
glucose and urine glucose excretion

A randomized open label feasibility study will be conducted in subjects with
Type II diabetes. The study will consist of a screening visit and 2 treatment
days. On the first study day, after IV radiotracer administration, a baseline
dynamic PET scan will be taken to measure selective uptake and accumulation in
the region of interest (ROI; kidney, aorta and part of the liver ).
On the second study day, after oral canagliflozin administration, a second IV
radiotracer dose will be administered followed by a second 90-minute dynamic
PET scan (post-drug). In this second scan, receptor binding sites are occupied
by canagliflozin, hence the reduction of radiotracer uptake compared to the
baseline scan can be used to determine the receptor occupancy based on the
binding potentials obtained from both scans. In all patients arterial plasma
samples will be taken after radiotracer administration, to quantify radiation
measure and free plasma concentrations of canagliflozin and its metabolites.
Subjects will receive one of 3 dosages of oral canagliflozin, 50, 100 or 300 mg
canagliflozin, with 3 patiens per dosage.

A single oral dose of 50, 100, 300mg of canagliflozin (see also study design).

Patients will be subjected to physical examination by the principal
investigator or delegate before inclusion. This physical examination entails a
routine investigation of heart, lungs and abdomen. A pregnancy test will be
performed in female participants of the study. Blood pressure will be monitored
during screening and on both study days. Body weight will be measured during
screening and both study days. On the first study day, a CT topogram will be
performed. At time=0 hours, patients will receive an intravenous (IV)
diagnostic dose of 18F-canagliflozin radiotracer followed by a 90-minute
dynamic PET scan. On the second study day, a CT topogram will be performed and
three dose groups will receive an oral dose of canagliflozin. At the
approximate time of maximal plasma canagliflozin concentration (tmax, 2.5h) a
second IV radiotracer dose will be administered immediately followed by a
second 90-minute dynamic PET scan. During the two treatment periods, 24-hour
urine will be collected. At screening and on both study days (prior to dosing)
a blood sample will be drawn by venepuncture for laboratory measurement (10 mL
each). During the two study days, in all patients, arterial plasma samples (10
samples of ~50 microlitre) will be taken after radiotracer administration, to
quantify radiation measure of 18F canagliflozin and its metabolites. For this
procedure an anaesthesiologist will place an arterial cannula under local
lidocain anaesthesia on both study days. Also, on the second study day, plasma
samples (10 samples of 4 mL) will be taken to quantify unlabelled plasma
concentrations of canagliflozin for the purpose of determining the
pharmacokinetic parameters (e.g clearance and volume of distribution) for each
subject. Over the entire duration of the study an amount of 285ml of blood will
be taken.
The total radiation exposure is 7.4 mSv over the entire duration of the trial.
This is classified as category 2B according to ICRP 62 and comparable to 3
times the background radiation dose per year.
There is no direct benefit to the patient*s health be expected from this study.
Participation in the study is on a free-will base. Patients will receive
restitution of all costs of transportation. Patients will not receive priority
for treatment of other diseases in the clinic during this study. Participation
in the proposed study is accompanied wil only minor risks, if any at all.