Feasibility Study to Assess Canagliflozin Distribution and Sodium‐Glucose Co‐Transporter 2 Occupancy Using [¹⁸F]Canagliflozin in Patients with Type 2 Diabetes

Sodium‐glucose co‐transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large interindividual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [ 18 F]canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes. We obtained two 90‐minute dynamic PET scans with diagnostic intravenous [ 18 F]canagliflozin administration and a full kinetic analysis in 7 patients with type 2 diabetes. Patients received 50, 100, or 300 mg oral canagliflozin ( n = 2:4:1) 2.5 hours before the second scan. Canagliflozin pharmacokinetics and urinary glucose excretion were measured. The apparent SGLT2 occupancy was derived from the difference between the apparent volume of distribution of [ 18 F]canagliflozin in the baseline and post‐drug PET scans. Individual canagliflozin area under the curve from oral dosing until 24‐hours (AUC P0‐24h ) varied largely (range 1,715–25,747 μg/L*hour, mean 10,580 μg/L*hour) and increased dose dependently with mean values of 4,543, 6,525, and 20,012 μg/L*hour for 50, 100, and 300 mg, respectively ( P = 0.046). SGLT2 occupancy ranged between 65% and 87%, but did not correlate with canagliflozin dose, plasma exposure, or urinary glucose excretion. We report the feasibility of [ 18 F]canagliflozin PET imaging to determine canagliflozin kidney disposition and SGLT2 occupancy. This suggests the potential of [ 18 F]canagliflozin as a tool to visualize and quantify clinically SGLT2 tissue binding.