Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects

• Published in: Clinical therapeutics Vol. 37; no. 7; pp. 1483 - 1492.e1
• Main Authors: Chen, Xia, MD, Hu, Pei, MD, Vaccaro, Nicole, BS, Polidori, David, PhD, Curtin, Christopher R., BS, Stieltjes, Hans, MSc, Sha, Sue, MD, PhD, Weiner, Sveta, MS, Devineni, Damayanthi, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2015; Elsevier Limited
• Subjects: Adolescent; Adult; Asian Continental Ancestry Group - statistics & numerical data; Blood Glucose - metabolism; Body mass index; canagliflozin; Canagliflozin - administration & dosage; Canagliflozin - adverse effects; Canagliflozin - pharmacokinetics; Cross-Over Studies; Diabetes; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Ethnicity; Female; Glomerular Filtration Rate - drug effects; Glucose; Glucosides - pharmacokinetics; Glycosuria - urine; Healthy Volunteers; Hormone replacement therapy; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacokinetics; Internal Medicine; Kidney - metabolism; Male; Medical Education; Metabolites; Middle Aged; Molecular weight; Nutrition research; pharmacodynamics; pharmacokinetics; Rodents; safety; sodium-glucose cotransporter 2 inhibitor; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Thiophenes - administration & dosage; Urine; Young Adult; pharmacokinetics; sodium-glucose cotransporter 2 inhibitor; pharmacodynamics; safety; canagliflozin
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2015.04.015

Abstract Purpose Canagliflozin, an orally active sodium–glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of canagliflozin in healthy Chinese subjects. Methods In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. Findings All participants are healthy Chinese adults. Mean AUC and Cmax of canagliflozin increased in a dose-dependent manner after single-dose administration (AUC0–∞ , 10,521 ng · h/mL for 100 mg, 33,583 ng · h/mL for 300 mg; Cmax , 1178 ng/mL for 100 mg, 4113 ng/mL for 300 mg). The mean apparent t½ and the median Tmax of canagliflozin were independent of dose (t½ , 16.0 hours for 100 mg, 16.2 hours for 300 mg; Tmax , ~1 hour). Mean CL/F and renal clearance of canagliflozin were comparable between the 2 doses. Mean plasma metabolite to parent molar ratios for Cmax and AUC0–∞ were similar with both doses. Canagliflozin decreased the 24-hour mean renal threshold for glucose, calculated by using measured creatinine clearance to estimate the glomerular filtration rate (67.9 and 60.7 mg/dL for canagliflozin 100 and 300 mg, respectively) and 24-hour increased urinary glucose excretion (33.8 and 42.9 g for canagliflozin 100 and 300 mg, respectively) in a dose-dependent manner; the 24-hour plasma glucose profile remained largely unchanged. No deaths, hypoglycemic events, or discontinuations due to adverse events were observed. Implications Pharmacokinetics (AUC and Cmax ) of canagliflozin increased in a dose-dependent manner after single oral doses of canagliflozin (100 and 300 mg) in these healthy Chinese subjects. Tmax and t½ of canagliflozin were independent of the dose. Canagliflozin decreased the 24-hour mean renal threshold for glucose and increased urinary glucose excretion in a dose-dependent manner; these results are consistent with those observed in other patient populations. Canagliflozin was generally safe and well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01707316.