Canagliflozin REnal Distribution Intervention Trial (CREDIT)

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a novel class of drugs used in the treatment of type 2 diabetes mellitus and they have shown to slow progression of diabetic kidney disease and to have beneficial effects on cardiovascular end points, in particular reduction of heart failure. However, the response of SGLT2 inhibitors on albuminuria and eGFR varies between individuals and about 20% of patients does not respond at all. Consequently, a considerable proportion of patients remain at high risk of progressive renal function loss. We hypothesize that the variability in drug response between individuals is the result of between individual variability in drug disposition to target tissues. To test this hypothesis we have synthesized an 18F PET radiotracer of the SGLT2 inhibitor canagliflozin, retaining the original molecular structure. As a first step, we will evaluate 18F-canagliflozin receptor specific binding, receptor occupancy, and optimal PET scanning time. As such, in this clinical feasibility study, we will generate essential PET data to optimize the design of a future clinical study in subjects with type 2 diabetes and microvascular complications.

We hypothesize that the underlying mechanisms of the varying response to a drug 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.

In this clinical feasibility study we will assess radiolabeled canagliflozin pharmacokinetic characteristics and determine specific receptor binding, receptor occupancy and optimal scanning time in patients with diabetes. The main objectives are;

To assess canagliflozin target (i.e. receptor) specific binding in vivo

To assess receptor occupancy of canagliflozin in vivo

During both study days, for all patients, after radiotracer drug administration, arterial plasma samples will be taken obtained by an automated sampler for radioactivity in full blood and plasma. After administration of oral canagliflozin 11 venous blood samples will be obtained for canagliflozin PK assessment. 24-hour urine will be collected for the measurement of 24-h glucose, protein, albumin, sodium, potassium, creatinine, and urea excretion at both study days. Plasma glucose will be measured after oral canagliflozin administration.

On the first study day, a non-diagnostic dose CT scan will be performed to optimally position the individual patient for the dynamic PET scan (e.g. with kidney, aorta and part of the liver inside the field of view) and attenuation correction, respectively. At time=0, patients will receive an intravenous diagnostic dose of 200Mbq 18F canagliflozin radiotracer followed by a 90-minute dynamic PET scan. At the second visit patients will receive an oral dose of 50, 100 or 300 mg canagliflozin (3 patients per dose group). At the approximate time of maximal plasma canagliflozin concentration (tmax, t=2.5h) a second intravenous radiotracer dose will be administered immediately followed by a second 90-minute dynamic PET scan. 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 measures of 18F canagliflozin and its metabolites and venous blood samples will be taken after oral canagliflozin administration to obtain plasma concentrations of canagliflozin.