Summary

• Mean absolute oral bioavailability of canagliflozin is approximately 65%.^1,2 Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics (PK) of canagliflozin; therefore canagliflozin may be taken without regard to food. However, based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that canagliflozin be taken before the first meal of the day.¹
• Peak plasma concentrations occurred 1 to 2 hours after a single dose administration of canagliflozin 100 mg and 300 mg in healthy subjects.¹
• The apparent terminal half-life is 10.6 hours for the 100 mg dose and 13.1 hours for the 300 mg dose.¹
• Canagliflozin is highly-protein bound (99%), mainly to albumin.¹
• O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UDP-Glucuronosyl Transferase (UGT) 1A9 and UGT2B4 to 2 inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (~7%) in humans.¹ The major human plasma metabolites are the ether (O)-glucuronides M7 and M5, and both are pharmacologically inactive with respect to sodium-glucose cotransporter-2 (SGLT2) and sodium-glucose cotransporter-1 (SGLT1) inhibition in vitro.³
• Canagliflozin is excreted in urine (30.5% of radioactive dose as O-glucuronide metabolites and <1% as unchanged drug) and feces (41.5% of radioactive dose as canagliflozin, 7% as a hydroxylated metabolite, and 3.2% as an O-glucuronide metabolite).¹
• Phase 1 studies conducted in adult patients with type 2 diabetes mellitus (T2DM), pediatric patients with T2DM, and healthy subjects evaluated several PK parameters, including plasma concentration of canagliflozin (and M7 metabolite), area under the plasma concentration-time curve (AUC), canagliflozin elimination half-life, and urinary excretion of canagliflozin.^2,4-8
• Other phase 1 studies evaluating the PK of canagliflozin in Japanese subjects^9-11, Chinese subjects¹², Indian subjects¹³, and nondiabetic, but renally- or hepatically-impaired subjects¹⁴ are available. Population PK model analyses were also conducted.^15,16

METABOLIC PATHWAY OF CANAGLIFLOZIN

O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to 2 inactive O-glucuronide metabolites (see Figure: Metabolic Pathway of Canagliflozin). CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (~7%) in humans.¹ The major human plasma metabolites are the ether (O)-glucuronides M7 (formed by UGT1A9) and M5 (formed by UGT2B4), and both are pharmacologically inactive with respect to SGLT2 and SGLT1 inhibition in vitro.  A minor oxidative metabolite (M9) is formed predominantly by CYP3A4-mediated hydroxylation.³

PK

Adult Patients with T2DM

Devineni et al (2012)⁷ evaluated the PK of canagliflozin 100 mg (once daily) and 300 mg (twice daily) in a randomized, double-blind, placebo-controlled, 28-day, 2-cohort, phase 1b study involving men and women with T2DM of at least 6 months duration. Patients received stable doses of insulin for 2 weeks with or without metformin, sitagliptin, and/or a thiazolidinedione.

• Fifteen patients in cohort 1 were randomized to receive canagliflozin 100 mg (N=10) or placebo (N=5) once daily before the morning meal. Fourteen patients in cohort 2 were randomized to receive canagliflozin 300 mg (N=10) or placebo (N=4) twice daily before the morning and evening meals.
• Time to maximum plasma concentrations (T_max) were 2.75 to 4.0 hours. The maximum canagliflozin plasma concentration administered after the second 300 mg dose was similar to plasma concentrations following the first dose.
• The canagliflozin elimination half-life was 14.7 hours for 100 mg once daily and 11.8 hours for 300 mg twice daily.

In another phase 1 study, Devineni et al (2013)⁴ evaluated the PK of canagliflozin 50 mg, 100 mg, and 300 mg once daily in 36 men and women (26 to 65 years of age) with T2DM (mean glycosylated hemoglobin [HbA1C]: 8.1) for 1 to 12 years. The study consisted of a 3-week screening phase, 3-week washout period, 2-day baseline phase, 7-day double-blind treatment phase (1:1:1:1 randomization to 50 mg, 100 mg, 300 mg, or placebo), and a 3-day follow-up phase.

• Mean plasma concentrations of canagliflozin and 2 major metabolites (M5 and M7) increased in a dose-dependent manner. Maximum plasma concentrations (C_max) for canagliflozin 100 mg and 300 mg on day 7 were 1227 and 4678 ng/mL, respectively. C_max for M5 metabolites in the 100-mg and 300-mg canagliflozin groups on day 7 were 559 and 1900 ng/mL, respectively. C_max for M7 metabolites in the 100 mg and 300 mg canagliflozin groups on day 7 were 1276 and 3122 ng/mL, respectively.
• Median T_max values were 1.5 to 2.0 hours for canagliflozin, 1.75 to 4.5 hours for the M5 metabolite, and 2.0 to 3.0 hours for the M7 metabolite for all doses on days 1 and 7.
• Canagliflozin terminal half-life was independent of dose and ranged from 14 to 16 hours on day 7. The terminal elimination half‐lives of M5 and M7 ranged from about 14 to 15 and 14 to 17 hours, respectively.
• Steady state of canagliflozin, M5, and M7 concentrations were achieved by day 4.
• Less than 1% of the dose was excreted in the urine as unchanged drug. Approximately 7% to 10% was excreted in urine as the M5 metabolite and approximately 21% to 32% was excreted as the M7 metabolite.
• There were no serious treatment‐emergent adverse events (TEAEs) and no patients discontinued from the study.

Pediatric Patients with T2DM

Tamborlane et al (2018)⁸ evaluated the PK, pharmacodynamics, and short-term safety and tolerability of canagliflozin in pediatric patients with T2DM in a phase 1, two-week, open-label, multiple-dose, multicenter, dose-finding study.

• Patients with T2DM aged 10 to 17 years who were on a stable regimen of metformin immediate-release monotherapy of ≥1000 mg/day for ≥8 weeks prior to screening were eligible for inclusion. Patients also had to have an estimated glomerular filtration rate of ≥90 mL/min/1.73 m² and an HbA1C level between 6.1% and 10.0%.
• Patients were enrolled into 2 cohorts sequentially (canagliflozin 100 mg and canagliflozin 300 mg).
• Placebo was administered on day-1, followed by 14 days of open-label treatment with either a single daily dose of canagliflozin 100 mg or canagliflozin 300 mg.
• A total of 17 patients (5 males and 12 females) participated in the study (canagliflozin 100 mg, n=8; canagliflozin 300 mg, n=9).
• Patient demographics and baseline characteristics were generally similar between groups. Mean age was 14.6 years, mean body weight was 107.2 kg, mean body mass index was 38.2 kg/m², mean HbA1C was 6.9%, 71% of patients were black/African American, and 24% of patients were Hispanic/Latino.
• Dose-dependent increases were observed in the PK of canagliflozin 100 mg and 300 mg, with C_max and AUC values similar to those observed in adults.
  • C_max was observed at 1.6 and 2.4 hours in the canagliflozin 100-mg group and 300-mg group, respectively. Mean C_max values were 9.5±4.3 and 10.9±4.4 ng/mL/mg, respectively, and corresponding mean AUC values were 61.9±17.7 and 94.6±41.4 h·ng/mL/mg, respectively.
• The elimination half-life was 11.3±2.5 hours and 15.2±6.9 hours in the canagliflozin 100-mg group and 300-mg group, respectively.
• On day 14, a decrease in mean 24-hour renal threshold for glucose to 84.6±13.8 mg/dL and 69.1±9.6 mg/dL was observed with canagliflozin 100 mg and 300 mg, respectively, consistent with reductions observed in adults.
• Mean 24-hour urinary glucose excretion increased from 5.3±10.5 g at baseline to 74.1±37.4 g with canagliflozin 100 mg, and from 0.1±0.04 g at baseline to 68.6±26.5 g with canagliflozin 300 mg.
• TEAEs were reported in 9/17 (52.9%) patients, with no apparent dose relationship (canagliflozin 100 mg, n=4; canagliflozin 300 mg, n=9). No deaths, serious TEAEs, or study drug discontinuations due to TEAEs were reported.

Healthy Subjects

Devineni et al (2014)² evaluated the absolute oral bioavailability as well as the PK and role of biliary excretion of canagliflozin in healthy male subjects in an open-label, single-center study.

• Nine healthy adult males received a single oral dose of canagliflozin 300 mg followed by a single intravenous (IV) infusion of [¹⁴C]-canagliflozin 10 mcg.
• Oral canagliflozin 300 mg was rapidly absorbed and reached a median T_max of 1.5 hours. Additionally, mean systemic exposure (AUC_∞), peak plasma concentration, and apparent half-life were 17,375 ng/mL, 2,504 ng/mL, and 11.6 hours, respectively.
• Comparison of AUC_∞ of oral and IV canagliflozin showed that mean absolute oral bioavailability of canagliflozin was 65%.
• Total cumulative biliary and renal excretion of radioactivity was 68.6% (34.1% feces, 34.5% urine) at 70 hours after the IV [¹⁴C]-canagliflozin dose.

In another study of healthy subjects (N=24), Devineni et al (2015)⁵ evaluated the effect of food on the PK of canagliflozin 300 mg tablets in an open-label, randomized, single-dose, 2-period crossover trial.

• Subjects were randomized (1:1) to receive either canagliflozin 300 mg once daily on days 1–4 under fasted condition in period-1, followed by a 10–14-day washout, and then canagliflozin 300 mg once daily on days 1–4 under fed condition in period-2, or vice versa. The absence of a food effect was to be concluded if the limits of the 90% confidence intervals (CIs) for the ratios of geometric mean ratios (GMRs) for AUC and C_max were between 80% and 125%.
• Mean plasma concentration-time profiles of canagliflozin were similar under fasted and fed conditions.
• Mean plasma concentration increased rapidly with a median T_max of 2 hours under both fed and fasting conditions; and mean half-life was 12.9 hours under fasting conditions and 12.6 hours under fed conditions.
• After canagliflozin administration, the GMRs of canagliflozin under the fed condition relative to the fasted condition for AUC_∞, AUC_last, and C_max were 108.09% (90% CI: 103.45, 112.95), 108.34% (90% CI: 103.77, 113.11), and 100.51% (90% CI: 89.47, 112.93), respectively. The 90% CIs for the GMRs between fed and fasting conditions were within the bioequivalence limits of 80-125% for AUC and C_max.
• TEAEs were more frequent under fasting conditions (36.4%; n=8/24) as compared to fed conditions (13.0%; n=3/24).

In an open-label, randomized, 3-period crossover study conducted in healthy subjects (N=24) to assess the dose proportionality of canagliflozin 50 mg and canagliflozin 100 mg and 300 mg under fasting conditions, PK parameters were found to increase proportionally with increase in dose from 50 mg to 300 mg.⁶

• All subjects were randomized (1:1:1) to receive either canagliflozin 50 mg, canagliflozin 100 mg, or canagliflozin 300 mg during the treatment period in a specified sequence with a 10–14-day washout in between each period.
• Following oral administration, canagliflozin was rapidly absorbed and peak plasma concentration was reached at a median of 1.5 hours for all 3 doses.
• Mean apparent half-life values ranged from 9-11 hours.
• Mean AUC_∞ and C_max values increased with increasing dose. The 90% CI of the slope of regression line for each dose-normalized parameter for C_max and AUC_∞ were within prespecified limits of -0.124 and 0.124.
• Most TEAEs were transient and mild, and 1 adverse event led to discontinuation.

The PK of oral canagliflozin and metabolites M7 and M5 were evaluated by Devineni et al (2015)¹⁸ in an open-label, single- and multiple-dose, parallel-group study of healthy, white, male and female subjects (N=27).

• Subjects were randomized to receive either canagliflozin 50 mg, 100 mg, or 300 mg (1:1:1).
• Mean plasma canagliflozin, M7, and M7 reached steady state within 4 days.
• Mean plasma concentrations of canagliflozin, M7, and M5 increased rapidly after single- and multiple-dose administration. The median T_max was 1 hour, 1.5-2 hours, and 2 hours, respectively.
• Mean C_max and AUC_∞ increased for canagliflozin and its metabolites in a dose-dependent manner after a single dose and at steady state.
• The half-life of canagliflozin, M7, and M5 was independent of dose and ranged from 9-12 hours after a single dose and 13-14 hours after multiple doses.
• Mean percentage of M7 and M5 recovered in urine over 48 hours ranged from 16%-22% and 8%-12%, respectively. Less than 1% was recovered as canagliflozin in urine.
• No significant accumulation was observed at any dose studied for canagliflozin, M7, or M5.
• Canagliflozin was well tolerated, with no serious adverse events or discontinuations due to adverse events.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 25 November 2024.