Summary

• Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics (PK) of canagliflozin; therefore, INVOKANA^® may be taken with or without food.^1,2
• Phase 1 studies report administering canagliflozin doses >200 mg 20 to 30 minutes before breakfast and observed a reduction in postprandial plasma glucose (PPG) over the first two hours.^3-5 Based on the potential to reduce PPG excursions due to delayed intestinal glucose absorption, it is recommended that INVOKANA^® be taken before the first meal of the day.^1,2
• A study of healthy subjects (N=24) evaluated the effect of food on the PK of canagliflozin 300 mg tablets in an open-label, randomized, single-dose, crossover trial. The administration of food did not have clinically significant effect on PK parameters.²
• A parallel-cohort, prospective, comparative, observational study has been published evaluating the tolerability of canagliflozin compared to sulfonylureas in type 2 diabetes mellitus (T2DM) patients who fasted during Ramadan.⁶

CLINICAL STUDIES

In the Phase 3 studies described in the INVOKANA^® Prescribing Information, canagliflozin was administered prior to the first meal of the day. This decision was based on reductions in PPG over the first two hours reported in Phase 1 studies^3-5 with canagliflozin >200 mg doses, which suggest additional glucose-lowering activity, via decreased glucose excursion post-meal, when canagliflozin is given prior to a meal.⁷

PHASE 1 STUDIES

Food Effect

In a randomized, parallel-group, comparison, open label study of hospitalized type 2 diabetes Japanese patients (N=30), Takebayashi et al (2017)⁸ evaluated the effects of food on the PK of canagliflozin 100 mg daily alone, then canagliflozin 100 mg daily in addition to teneligliptin 20 mg daily.

• Patients were randomized 1:1 to canagliflozin or control based on hemoglobin A1C (HbA1c), body mass index, gender, and age. All patients were hospitalized on Day 1, after enrollment.
• On Day 2, patients in the canagliflozin group took the dose of canagliflozin after the first meal test (before lunch). The canagliflozin-treated patients took the canagliflozin dose 30 minutes before breakfast or test meal thereafter.
• On Day 5, patients in the canagliflozin and control groups took teneligliptin before lunch. Both groups took teneligliptin 30 minutes before breakfast or meal test thereafter.
• While hospitalized, patients received diet and exercise therapy.
• Results found that canagliflozin administration before meals significantly decreased the area under the curve (AUC) for plasma glucose (P<0.0001) and significantly increased the AUC of plasma active GLP-1 (P<0.0001) both independently and after teneligliptin.⁸
• Canagliflozin significantly decreased the AUC for serum insulin from baseline to day 3 (P=0.0180). After adding teneligliptin, the AUC for insulin was elevated. Canagliflozin did not change the AUC of plasma active glucose-dependent insulinotropic peptide.⁸

In a study of healthy subjects (N=24), Devineni et al (2014)² 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 limits of the 90% CIs for the ratios of geometric mean ratios (GMRs) for AUC and maximum plasma concentration (C_max) were between 80% and 125%.
• All subjects fasted for at least 10 hours overnight. For fed state, subjects were provided with a standardized high-fat breakfast 30 minutes prior to dosing.
• Twenty-two subjects were under the fed state and 21 under the fasting state.
• 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 t_1/2 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 from time 0 to infinite time (AUC_∞), AUC from time 0 to the time of the last quantifiable concentration (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.
• Treatment emergent adverse events were more frequent under fasting conditions (36.4%; n=8/24) as compared to fed conditions (13.0%; n=3/24).

Meal-Timing

Sha et al (2011)³ conducted a double-blind, randomized, placebo-controlled, ascending-dose phase 1 study evaluating the safety, tolerability and pharmacodynamics (PD) of canagliflozin in healthy men (N=63) randomized to receive canagliflozin (n=48) or placebo (n=15).

• Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg once daily or 400 mg twice daily) was administered to 8 cohorts (6 subjects/cohort: Canagliflozin; 2 subjects/cohort: placebo). Each subject received only one dose of study medication.
• Three standardized meals were provided at 30 minutes, 4.5 hours and 10.5 hours after the day 1 morning dose (for the 400 mg twice daily cohort, the evening meal was given at 30 minutes after the evening dose).
• At canagliflozin doses >200 mg administered 30 minutes before breakfast, a reduction in the rate of PPG absorption was observed over the first 2 hours as compared with canagliflozin 100 mg or 200 mg.
• This effect of canagliflozin doses >200 mg on PPG over the first 2 hours was subsequently confirmed by other Phase 1 studies^4,5 that administered the dose 20 minutes before breakfast. Polidori et al (2013)⁴ reported that canagliflozin 300 mg slowed the rate of PPG absorption over the first 2 hours as compared to placebo in healthy subjects. Stein et al (2014)⁵ reported that canagliflozin 300 mg slowed the rate of PPG absorption over the first 2 hours as compared to canagliflozin 150 mg and placebo in patients with T2DM.

Polidori et al (2013)⁴ showed in a randomized, double-blind, placebo-controlled, two-period crossover study that in healthy male subjects, a single 300 mg dose of canagliflozin administered before 600 kcal meal reduced PPG excursions (N=20).

• Subjects were randomized to either canagliflozin 300 mg in treatment period 1, followed by matching placebo in period 2, or vice versa, with a washout period of 7–21 days between treatment periods.
• Mean PPG ΔAUC values were ~44%, 35%, and 26% lower during the 0- to 1-hour, 0- to 2-hours, and 0- to 6-hours post meal intervals, respectively, after administration of canagliflozin 300 mg compared to placebo.
• Treatment with canagliflozin reduced the amount of oral glucose absorption (AUC rates of appearance of oral glucose [R_aO]) compared with placebo by 31% over the 0- to 1-hour interval (P=0.001) and by 20% over the 0- to 2-hour interval (P=0.01). This was followed by a 34% increase in AUC R_aO in the 2- to 6-hour interval for canagliflozin 300 mg compared with placebo. The AUC R_aO over 0- to 6-hours was only ~6% lower for canagliflozin compared with placebo (P=0.003).
• Postprandial plasma insulin ΔAUC were 43%, 43%, and 33% lower during the 0- to 1-hour, 0- to 2-hours, and 0- to 6-hours after meal intervals, respectively, for canagliflozin compared to placebo.

Stein et al (2014)⁵ conducted a double-blind, placebo-controlled, randomized, crossover study evaluating the effects of canagliflozin on PPG in patients with T2DM inadequately controlled with metformin (N=37).

• T2DM patients were enrolled and randomly assigned to a treatment sequence (ADBC [n = 9], BACD [n = 9], CBDA [n = 8], and DCAB [n = 11]). Each treatment period lasted 3 days, followed by a washout period of 14 days.
  • Treatments were as follows: Treatment A, placebo/placebo (PBO/PBO); Treatment B, canagliflozin 300 mg/placebo (C300/PBO); Treatment C, canagliflozin 300 mg/canagliflozin 300 mg (C300/C300); Treatment D, canagliflozin 300 mg/canagliflozin 150 mg (C300/C150).
  • Patients were also on stable metformin therapy throughout the study.
• Patients received their first dose of study drug on Day 2 of the 3-day treatment period prior to the morning meal after an overnight fast of ≥8 hours. Patients received the second dose for that treatment period on the morning of Day 3, 20 minutes prior to starting the meal for the mixed-meal tolerance test (MMTT).
• The primary efficacy endpoint was the between-treatment differences in total PPG AUC_0-2h during the MMTT for C300/C300 compared with PBO/PBO.
• Total PPG AUC_0–2h was reduced in all canagliflozin treatment groups, with the C300/C300 group providing a significant reduction compared to placebo (-15.7%; CI -19.1% to -12.1%; P<0.001).
• C300/C300 significantly lowered PPG ΔAUG_0–2h compared with C300/PBO (P=0.012); however, C300/C150 did not significantly decrease PPG ΔAUC_0–2h compared to C300/PBO (P=0.718).
• AEs were similar across treatment groups, and no serious AEs, AEs leading to discontinuation, or deaths were reported.

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 12 September 2024.