Scientific Publications by FDA Staff

J Clin Pharmacol 2015 Jun;55(6):647-56

Canagliflozin use in patients with renal impairment--utility of quantitative clinical pharmacology analyses in dose optimization.

Khurana M, Vaidyanathan J, Marathe A, Mehrotra N, Sahajwalla CG, Zineh I, Jain L

Canagliflozin (INVOKANATM ) was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Canagliflozin inhibits renal sodium-glucose co-transporter 2 (SGLT2), thereby, reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Given the mechanism of action of SGLT2 inhibitors, we assessed the interplay between renal function, efficacy (HbA1c reduction) and safety (renal adverse reactions). The focus of this manuscript is to highlight the FDA's quantitative clinical pharmacology analyses that were conducted to support the regulatory decision on dosing in patients with renal impairment (RI). The metrics for assessment of efficacy for T2DM drugs is standard; however, there is no standard method for evaluation of renal effects for diabetes drugs. Therefore, several analyses were conducted to assess the impact of canagliflozin on renal function (as measured by eGFR) based on available data. These analyses provided support for approval of canagliflozin in T2DM patients with baseline eGFR >/= 45 mL/min/1.73 m2 , highlighting a data-driven approach to dose optimization. The availability of a relatively rich safety dataset (i.e., frequent and early measurements of laboratory markers) in the canagliflozin clinical development program enabled adequate assessment of benefit-risk balance in various patient subgroups based on renal function.