International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 3/2015 (256-264)
Original ©2015 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP202233 e-pub: December 29, 2014
Effect of food on the pharmacokinetics of canagliflozin/metformin (150/1,000 mg) immediate-release fixed-dose combination tablet in healthy participants Joseph Murphy1, Shean-Sheng Wang1, Hans Stieltjes2, Ewa Wajs2, and Damayanthi Devineni1 1Janssen
Research & Development, LLC, Raritan, NJ, USA, and & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium
2Janssen Research
Key words food effect – canagliflozin – metformin – fixed-dose combination – pharmacokinetics – sodium-glucose co-transporter 2 inhibitor
Received August 12, 2013; accepted October 21, 2014 Correspondence to Dr. Damayanthi Devineni Janssen Research & Development, LLC, 920 Route 202, Raritan, NJ 08869, USA [email protected]
Abstract. Objective: To assess the effect of food on the pharmacokinetics (PK) of canagliflozin and metformin following administration of a canagliflozin/metformin (150/1,000 mg) immediate-release (IR) fixed-dose combination (FDC) tablet. Methods: A randomized, open-label, singlecenter, single-dose, 2-period, 2-sequence crossover study was conducted in healthy participants. Participants were randomized to 2 sequences of fasted and fed (or vice versa) administration of one 150/1,000 mg canagliflozin/metformin IR FDC, with 10 – 14 day washout between treatments. PK parameters (AUC, Cmax, tmax, t1/2) were assessed for canagliflozin and metformin. Safety was evaluated. Results: When comparing the IR FDC tablet administered with and without food, PK parameters of canagliflozin were bioequivalent as the 90% confidence intervals (CIs) for log-transformed AUClast, AUC∞, and Cmax were within the bioequivalence limits of 80 – 125%. For metformin, overall exposure was similar under fed and fasted conditions as geometric mean ratios for AUC and associated 90% CI were contained within the bioequivalence limits, but geometric mean Cmax decreased by 16% in the fed compared to fasted state. Both treatments were well tolerated with similar adverse events and most common were gastrointestinal events, generally attributed to metformin. Conclusions: Food did not affect canagliflozin bioavailability parameters (Cmax and AUCs) or AUCs of metformin. The Cmax of metformin was decreased by 16%, which is not considered clinically meaningful. The canagliflozin/ metformin FDC tablet is recommended to be taken with meals to reduce the symptoms of gastrointestinal intolerability associated with metformin.
Introduction Oral antidiabetic combination therapy is emerging as the standard of care in long-term clinical management of type 2 diabetes mellitus (T2DM) in adults. Canagliflozin (Invokana™ ) is a new orally bioavailable selective inhibitor of sodium-glucose co-transporter 2 (SGLT2) that acts on proximal renal tubules to decrease renal glucose reabsorption and increase urinary glucose excretion, thereby decreasing plasma glucose levels in patients with hyperglycemia [1, 2]. Canagliflozin is approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM in numerous countries worldwide. The recommended dose of canagliflozin is 100 or 300 mg once daily [3, 4, 5, 6, 7]. For many decades, metformin has been the recommended first-line oral antidiabetic therapy in management of T2DM in patients whose hyperglycemia is not adequately controlled by diet alone [8]. Metformin primarily acts by decreasing hepatic gluconeogenesis and improving insulin sensitivity [9]. Metformin can be prescribed up to maximum daily doses of 2,500 mg in adults and is available as immediate-release (IR) tablets of metformin hydrochloride (HCl) at 500, 850, and 1,000 mg dose strengths [10, 11]. Based on the position statement by the American Diabetes Association and the European Association for the Study of Diabetes, for patients who are inadequately controlled with metformin monotherapy, additional antihyperglycemic agents with complementary mechanisms of action may be prescribed [8]. Canagliflozin has a unique insulin-inde-
Effect of food on the pharmacokinetics of canagliflozin/metformin
pendent mechanism of action [12] that may provide new treatment approaches for T2DM as add on combination with metformin. In clinical studies of patients with T2DM, canagliflozin 300 mg was administered as addon to background metformin or combination of metformin plus sulfonylurea, and demonstrated significant reduction in HbA1c from baseline to week 52 compared with respective active controls, glimepiride, and sitagliptin [13, 14, 15, 16]. Canagliflozin 100 and 300 mg improved glycemic control, reduced body weight and was generally well tolerated in patients with T2DM inadequately controlled on metformin plus pioglitazone over 52 weeks [17]. A fixed-dose combination (FDC) tablet containing both canagliflozin and metformin in a single IR tablet offers improved patient compliance by simplifying administration and reducing pill burden. The canagliflozin (50 and 150 mg)/metformin (850 and 1,000 mg) IR FDC tablet has received regulatory approval in the European Union and the United States (50 and 150 mg/500 and 1,000 mg) for the treatment of adults with T2DM to improve glycemic control in patients not adequately controlled on their maximally tolerated doses of metformin alone or combined with other glucose lowering medicinal products including insulin, and patients already treated with combination of canagliflozin and metformin as separate IR tablets [18]. Canagliflozin/metformin IR FDC tablets or co-administration of single component IR tablets were established to be bioequivalent and are considered therapeutically equivalent and interchangeable in clinical practice [19]. Administration of food with a drug may alter the drug’s pharmacokinetics (PK) due to changes in drug absorption and metabolism resulting from possible factors such as delay in gastric emptying, changes in gastrointestinal fluid pH, and stimulation of bile flow in the gut affecting drug solubility and rate of dissolution [20, 21]. In addition, food-drug interaction may affect drug clearance and metabolism through changes in the splanchnic blood flow and plasma protein binding and modulation of drug-metabolizing enzymes [22, 23]. Therefore, it is important to establish the impact of food on the oral bioavailability and PK of the canagliflozin/ metformin IR FDC tablet in order to understand the clinical relevance of food-induced
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changes on both canagliflozin and metformin efficacy and tolerability and determine optimum timing of drug administration relative to meal times. The present clinical study investigated the effect of concomitant intake of a standardized, high-fat breakfast relative to fasted state on the PK of the canagliflozin/ metformin IR FDC tablet. The highest strength of the FDC tablet manufactured at 150/1,000 mg for twice a day dosing was investigated in accordance with US FDA and EMA guidelines on food-effect bioavailability and fed bioequivalence studies [24, 25], and similarly designed food effect studies on other antidiabetic agents formulated as FDC with metformin [26, 27, 28].
Methods Study population Men and women aged 18 – 55 years, who were considered healthy based on medical history, physical examination, and clinical laboratory evaluations, were enrolled in this study. Participants had a body mass index (BMI) of 18 – 30 kg/m2, body weight ≥ 50 kg, and blood pressure between 90 and 140 mmHg. Pregnant or breast feeding women were excluded. Individuals with a history of smoking, drug or alcohol abuse, and known allergy to the study drug were excluded. Participants refrained from taking any over-the-counter or prescription medications (with the exception of paracetamol, oral contraceptives, and hormonal replacement therapy) for at least 14 days prior to first drug administration and throughout the study. The protocol for the study was approved by an Institutional Review Board at the study site (Quintiles Phase One Services, KS, USA) and the study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki and in accordance with International Conference on Harmonisation Good Clinical Practice guidelines, applicable regulatory requirements, and in compliance with the protocol. All participants provided written informed consent to participate in the study.
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Study design and treatments This was a randomized, open-label, single-center, single-dose, 2-period, 2-sequence crossover study (NCT01459094) consisting of 3 phases: a screening phase of up to 28 days (day –22 through day –2); an open-label treatment phase of up to 19 days (including a washout period of 10- to 14-days between day 1 of each treatment period), and a follow-up phase of up to 10 days after day 4 of period 2 or at early withdrawal. On day 1 of treatment period 1, all participants were randomized (1 : 1) to receive either reference treatment A (fasting conditions) in period 1, followed by test treatment B (fed condition) in period 2 (sequence AB) or vice versa (BA). Participants received a single canagliflozin/metformin IR FDC tablet containing 150 mg of canagliflozin and 1,000 mg of metformin at each treatment period. Following an overnight fast of at least 10 hours, study drug administration occurred at approximately the same time each morning. Participants in reference treatment A (fasted) received study drug without food and participants in test treatment B (fed) received study drug 30 minutes after starting a standardized high-fat breakfast which participants were to complete during the allotted time. Study drug was administered with 240 mL of noncarbonated water. No food was allowed for at least 4 hours postdose in either treatment and water was withheld 1 hour before and after study drug administration with the exception of the water given with study medication.
Pharmacokinetic evaluations Sample collection A blood sample collection period of 72 hours for canagliflozin and 24 hours for metformin were used given the estimated 13- to 23-hour elimination half-life of canagliflozin and the estimated 6-hour half-life of metformin. Venous blood samples (2 mL for canagliflozin and 2 mL for metformin) for determination of canagliflozin and metformin plasma concentrations were collected in glass or plastic K2EDTA-containing tubes (e.g., Vacutainer®) at predose, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36 (canagliflozin only), 48 (canagliflozin only), and 72 (cana-
gliflozin only) hours postdose on day 1 of each treatment period. The samples were centrifuged at room temperature (10 minutes at 1,300 g) to obtain plasma. All plasma samples were stored at or below –20 °C until transferred to a bioanalytical facility. Analytical methods Plasma canagliflozin concentrations were determined with 13C6-canagliflozin as internal standard (IS) using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method at PRA International (Assen, The Netherlands). The HPLC system consisted of a Shimadzu LC-10Advp pump with Shimadzu SIL-HTC autosampler (Shimadzu Corporation, Kyoto, Japan). An API4000 mass spectrometer with a TurboIonsprayTM Interface (AB SCIEX, MA, USA) in the positive ion mode was used for MS determination. Multiple reaction monitoring (MRM) transitions were m/z 462.1 → 267.0 and 468.1 → 273.0 for canagliflozin and IS, respectively. The method for canagliflozin plasma determination used a liquid-liquid extraction with tert-butylmethylether, followed by chromatography with 30% ammonium acetate (0.01 M) and 70% methanol as the mobile phase. The flow rate was 0.25 mL/min on a Waters XBridgeTM C18 column (5 cm × 2.1 mm, 3.5-µm particle size), kept at 30 °C. The validated quantification range was 5.0 – 5,000 ng/mL. Plasma metformin concentrations were determined with 2H6-metformin as IS. The same LC-MS/MS system as for the canagliflozin assay was used, but with an API3000 mass spectrometer, in the positive ion mode. MRM transitions were m/z 130.1 → 70.9 and 136.0 → 77.0 for metformin and metformin IS, respectively. The sample preparation consisted of a protein precipitation with acidic (formic acid) acetonitrile, followed by gradient ion-pair chromatography with 0.02 M hexafluorobutyric acid in 0.01 M ammonium acetate (A) and acetonitrile (B), from at 5% to 27.5% B in 3 minutes. The flow rate was 0.3 mL/min over a Waters XBridgeTM Shield RP18 column (5 cm × 2.1 mm, 3.5-µm particle size), kept at 40 °C. The validated quantification range was 5.0 – 2,500 ng/mL. The validation was performed according to FDA guidance for bioanalysis [29,
Effect of food on the pharmacokinetics of canagliflozin/metformin
30]. This included within- and between-run precision and accuracy, selectivity, matrix effect, recovery, incurred sample reproducibility and stability (blood, plasma, processed sample). All validation results were within predefined acceptance criteria. The storage period between sample collection and analysis was covered by the available long-term stability data for the analytes in the presence of the other analyte (for canagliflozin 762 days and for metformin 190 days at –20 °C). Pharmacokinetic analyses The following plasma PK parameters were determined for canagliflozin and metformin based on the individual participant plasma concentration-time data, using actual sampling times via non-compartmental methods using validated WinNonlin® software Version 5.2.1 (Pharsight Corporation, Mountain View, CA, USA): maximum observed plasma concentration (Cmax), time to reach maximum observed plasma concentration (tmax), terminal elimination half-life (t1/2) associated with the terminal slope (λz) of the semilogarithmic drug concentrationtime curve, calculated as 0.693/λz, area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast), area under the plasma concentration-time curve from time 0 to infinite time (AUC∞), calculated as the sum of AUClast and Clast/λz, in which Clast is the last observed quantifiable concentration and λz is the terminal slope of the semilogarithmic drug concentration-time curve.
Safety assessments Safety evaluations were based upon the type, incidence, and severity of treatmentemergent adverse events (TEAEs) reported throughout the study, and on clinical laboratory tests, vital sign measurements, physical examinations, and 12-lead electrocardiograms (ECG) assessed at pre-defined time points.
Statistical analyses Sample size The intra-participant coefficient of variation (CV) of AUCs and Cmax were estimated
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to be no more than 10% and 25%, respectively for canagliflozin, and no more than 20% for both AUCs and Cmax for metformin. Using an intra-participant CV of 10% and 25% for AUCs and Cmax for canagliflozin, and the simple size of 20 participants to complete the study, the ratio of geometric mean AUC and Cmax of canagliflozin with food to without food would fall within 95 – 106% and 87 – 115%, respectively, of the true value with 90% confidence. Similarly, using an estimated intra-participant CV of 20% for AUCs and Cmax, respectively for metformin, a sample size of 20 participants would be sufficient for the ratio of geometric mean AUCs and Cmax of metformin with food to without food to fall within 90% to 112% of the true value with 90% confidence. Planned enrollment was 24 participants to ensure 20 participants completed the study. Statistical comparison The primary PK parameters of interest for the statistical analysis were the log-transformed canagliflozin and metformin AUC∞, AUClast and Cmax values. A mixed-effects modelling (Proc Mixed procedure in SAS (SAS Institute, version 9.2, Cary, NC, USA)) appropriate for crossover design was fitted to the PK parameter of interest. The model included treatment (fed and fasted), period (periods 1 and 2), and treatment sequence (treatment sequences 1 and 2) as fixed effects and participant as a random effect was applied to estimate the least squares mean of each treatments and the corresponding intra-participant variance. Using these estimated least squares means and intra-participant variances, the 90% confidence interval (CI) for the difference in means on a log scale between treatment A and B were constructed. The limits of the CI were retransformed using antilogarithms to obtain the 90% CI for the ratios of the mean values for AUCs and Cmax of the test (fed) to reference (fasted) formulation. Only data from participants who completed the study were included in the statistical analysis. If 1 of the PK parameters of interest was not estimable for a given participant in 1 or more periods, then that participant’s data was not to be included in the statistical analysis of that particular parameter.
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Table 1. Summary statistics for geometric means and ratio of geometric means with corresponding 90% confidence intervals (CIs) for canagliflozin pharmacokinetic parameters following administration of single dose of canagliflozin/metformin IR FDC tablet (150/1,000 mg) in the fed and fasted state. Parameter
Geometric mean Fed (test) Fasted (ref) n = 24 n = 24 Cmax (ng/mL) 1,325 1,463 12,612 11,307 AUClast (ng×h/mL) 13,117 11,650 AUC∞ (ng×h/mL)a 3.5 (1.0 – 6.0) 1.5 (1.0 – 5.0) tmax (h)b 21.5 (7.48) 19.8 (6.30) t1/2 (h)c
Geometric mean ratio (%) (90% CI) (test/reference) 90.6 (80.7 – 101.7) 111.5 (107.2 – 116.0) 112.6 (108.0 – 117.3)
IR = immediate-release; FDC = fixed dose combination; AUClast = area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration; AUC∞ = area under the plasma concentration-time curve from time 0 to infinite time; CI = confidence interval; Cmax = maximum observed plasma concentration; tmax = time to reach Cmax; t1/2 = elimination half-life. an = 22; b tmax, reported as median (range); ct1/2, reported as arithmetic mean (SD); n = 23.
TEAEs were summarized by treatment within each body system and for each preferred term. Results of clinical laboratory tests, vital signs, and ECG parameters were summarized using descriptive statistics.
Results Study disposition and demographics A total of 24 participants (15 men, 9 women) were enrolled and all completed both fasted and fed treatment sequences. Participants were Black or African American (14, 58%), White (8; 33%), or American Indian or Alaska Native (2, 8%). Mean (SD) age was 31.7 (10.9) years, weight 76.3 (9.0) kg, and BMI 25.4 (2.5) kg/m2. The demo-
graphic and baseline characteristics of participants in the 2 treatment sequence groups were comparable in terms of the mean age, weight, BMI and number of men and women.
Pharmacokinetic analyses Canagliflozin Following administration of the canagliflozin/metformin FDC IR tablet under fed and fasting conditions, the PK parameters for canagliflozin were similar for both treatments (Table 1). The fed-to-fasted geometric mean ratios (GMRs) and the corresponding 90% CI for AUClast, AUC∞, and Cmax were 111.5% (CI: 107.2, 116.0), 112.6% (CI: 108.0, 117.3), and 90.6% (CI: 80.7, 101.7), respectively. The 90% CIs for the GMRs of canagliflozin treatment under fed vs. fasted conditions were contained within the bioequivalence limits of 80% to 125% for Cmax and AUCs. The mean plasma canagliflozin concentrations following oral administration of the canagliflozin/metformin FDC tablet with or without food are shown in Figure 1A. The median tmax of canagliflozin was delayed following administration under fed conditions compared with fasted conditions (3.5 and 1.5 hours, respectively). However, a prolongation in tmax without a decrease in overall systemic exposure (AUC) is not considered clinically relevant. Mean apparent t1/2 values of canagliflozin were 19.8 hours and 21.5 hours in participants under fasting and fed conditions, respectively.
Figure 1. Mean (+SD) plasma concentration-time profiles for (A) canagliflozin and (B) metformin following administration of canagliflozin/metformin IR FDC tablet in the fed and fasted state. Conc = concentration; SD = standard deviation.
Effect of food on the pharmacokinetics of canagliflozin/metformin
Table 2. Summary statistics for geometric means and ratio of geometric means with corresponding 90% CI for metformin pharmacokinetic parameters following administration of single dose of canagliflozin/metformin IR FDC Tablet (150/1,000 mg) in the fed and fasted state. Parameter
Geometric mean Fed (test) Fasted (ref) n = 24 n = 24 Cmax (ng/mL) 1,373 1,643 10,908 10,951 AUClast (ng×h/mL) 11,222 11,228 AUC∞ (ng×h/mL) 3.0 (1.5 – 5.0) 2.0 (1.0 – 3.0) tmax (h)a 4.3 (0.41) 4.5 (0.71) t1/2 (h)b
Geometric mean ratio (%) (90% CI) (test/reference) 83.6 (77.2 – 90.5) 99.6 (91.9 – 108.0) 100.0 (92.3 – 108.2)
IR = immediate-release; FDC = fixed dose combination; AUClast = area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration; AUC∞ = area under the plasma concentration-time curve from time 0 to infinite time; CI = confidence interval; Cmax = maximum observed plasma concentration; tmax = time to reach Cmax; t1/2 = terminal elimination half-life. a tmax = reported as median (range), bt1/2 = reported as arithmetic mean (SD).
Metformin The PK parameters for metformin demonstrated that the metformin exposure was similar for the FDC tablet under fed and fasted condition (Table 2). The GMRs for metformin AUClast and AUC∞ and the associated 90% CI were 99.6% (CI: 91.9, 108.0) and 112.6% (CI: 108.0 – 117.3), respectively, and were contained within the bioequivalence limits of 80 – 125% indicating that AUCs for metformin were not affected by food. However, the geometric mean Cmax of metformin decreased by 16% in the fed as compared to the fasted state and did not meet the bioequivalence criteria (GMR of Cmax: 83.6%; 90% CI: 77.2, 90.5) (Table 2). The absorption phase of plasma metformin concentrations-time profiles was lower following administration of the canagliflozin/metformin FDC tablet under fed as compared to the fasted state (Figure 1B). Median tmax was 2.0 hours following administration of the FDC tablet without food (range 1.0 – 3.0 hours) and 3.0 hours after coadministration with food (range 1.5 – 5.0 hours). Mean apparent t1/2 of metformin was 4.46 hours under fasting conditions and 4.32 hours under fed conditions.
Safety and tolerability There were no deaths, other serious adverse events, or discontinuations due to adverse events. The incidence of TEAEs was
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the same after fasted and fed administration of the FDC tablet (n = 16; 66.7% in each treatment). The incidence of different TEAEs within each system organ class was comparable after both fasted and fed treatment. The most commonly reported TEAEs following both treatments were gastrointestinal disorders (14/24 (58.3%)). Overall, the most common TEAE was diarrhea, with the same incidence in both treatments (8/24 (33.3%)). The majority of gastrointestinal adverse events were judged by the investigator as very likely related to the administered treatment. There were no hypoglycemic events reported. There were no treatment-related changes from baseline in mean vital sign measurements, ECG parameters, or physical examinations, or in any of the routine clinical laboratory safety tests (i.e., hematology, chemistry, and urinalysis) that were considered to be clinically significant. Overall, no new, unexpected, or unusual safety signals were noted.
Discussion The present study evaluated the effect of food on the PK of the canagliflozin/metformin FDC IR tablet (150/1,000 mg) in healthy participants. For the fed condition, a single dose of the FDC tablet was administered 30 minutes after the start of a standardized, high-fat breakfast as compared to the fasted condition. Administration of the canagliflozin/metformin FDC tablet with food did not meaningfully alter the PK parameters of canagliflozin relative to the fasted state as the 90% CIs for GMR’s for AUClast, AUC∞, and Cmax were contained within the bioequivalence limits of 80 – 125%. The median tmax of canagliflozin was slightly delayed under fed as compared to fasted condition consistent with delay in rate of gastric emptying following ingestion of a high-fat meal and is not considered clinically relevant since its overall systemic exposure was unchanged. These results are consistent with the clinical findings of a separate food effect study that demonstrated oral bioavailability of single component 300 mg canagliflozin IR tablet was not impacted by ingestion of food [31]. This also indicates that the IR FDC formulation of canagliflozin with metformin did
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not produce a different food related change in its bioavailability than observed from the single agent canagliflozin IR tablet. The extent of absorption (AUCs) of metformin was similar between fasted and fed conditions as the 90% CIs for GMRs of metformin AUCs were within the bioequivalence limits of 80 – 125%. The mean Cmax of metformin was decreased by 16% and its median tmax delayed by about 1 hour following administration under fed conditions as compared to fasted condition. However, the small decrease in metformin Cmax under fed condition is not considered clinically important as AUC rather than Cmax is considered to be responsible for metformin antihyperglycemic effect [32]. This finding is consistent with results of other clinical studies in which co-administration with food of a metformin HCl IR tablet alone [33], or as an IR FDC tablet with other antidiabetic agents [26, 27, 28], resulted in reduced Cmax by 15 – 39% and delayed tmax by 0.5 – 1.5 hours. In one study, AUC of 850 mg metformin IR tablet decreased by ~ 25% [33]. Administration of a single dose of canagliflozin/metformin (150/1,000 mg) IR FDC tablet to healthy participants was well tolerated. The most commonly reported TEAEs were gastrointestinal disorders with similar incidence in the fed and fasted states and largely characteristic of the metformin component of the FDC tablet. Although the effect of food induced changes on the PK of canagliflozin/metformin FDC IR tablet was not clinically relevant, as metformin HCl IR is recommended to be administered with a meal to reduce the incidence of gastrointestinal side effects, it is also recommended that canagliflozin/metformin (150/1,000 mg) IR FDC tablet be taken with a meal to reduce gastrointestinal intolerability associated with metformin [10, 11].
and a small decrease in mean Cmax of metformin under the fed condition is not considered clinically relevant. Metformin HCl IR is recommended to be administered with a meal to reduce the incidence of gastrointestinal side effects, and therefore the intended mode of administration for the canagliflozin/metformin IR FDC tablet is similarly with meals.
Acknowledgments We acknowledge Dr. Bradford Challis (Janssen Research & Development, LLC) for providing writing assistance for the development of this manuscript. We thank Nicole Vaccaro (Janssen Research & Development, LLC) for generating figures. We thank the study participants, without whom the study would never have been accomplished, and the investigator Dr. Eleanor Lisbon (United States) for her participation in the study.
Conflict of interest The study presented in this report was supported by Janssen Research & Development, LLC. All authors are employees of Janssen Research & Development, LLC or of Janssen Research & Development, A division of Janssen Pharmaceutica NV, and hold stock in the company.
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Conclusion Administration of the canagliflozin/metformin (150/1,000 mg) IR FDC tablet with food did not alter to a clinically relevant extent the PK parameters of canagliflozin relative to the fasted state. Food did not affect the extent of absorption (AUCs) of metformin
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[16] Wilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, Usiskin K, Law G, Black S, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013; 67: 1267-1282. CrossRef PubMed [17] Forst T, Guthrie R, Goldenberg R, Yee J, Vijapurkar U, Meininger G, Stein P. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab. 2014; 16: 467-477. CrossRef PubMed [18] European Commission http://ec.europa.eu/health/ documents/community-register/html/newproc. htm#h. Last accessed on April 15, 2014. [19] Devineni D, Curtin C, Ariyawansa J, Weiner S, Rusch S, Stielties H, Vaccaro N, Shalayda K, Murphy J, DiProspero N, Wajs E. Bioequivalence of canagliflozin/metformin fixed-dose combination immediate release tablets compared with concomitant administration of single-components of canagliflozin and metformin in healthy fed participants. J Bioequiv Availab. Accepted for publication. [20] Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res. 2008; 25: 1663-1676. CrossRef PubMed [21] Persson EM, Gustafsson AS, Carlsson AS, Nilsson RG, Knutson L, Forsell P, Hanisch G, Lennernäs H, Abrahamsson B. The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids. Pharm Res. 2005; 22: 2141-2151. CrossRef PubMed [22] Gu CH, Li H, Levons J, Lentz K, Gandhi RB, Raghavan K, Smith RL. Predicting effect of food on extent of drug absorption based on physicochemical properties. Pharm Res. 2007; 24: 1118-1130. CrossRef PubMed [23] Yasuji T, Kondo H, Sako K. The effect of food on the oral bioavailability of drugs: a review of current developments and pharmaceutical technologies for pharmacokinetic control. Ther Deliv. 2012; 3: 81-90. CrossRef PubMed [24] Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). Guidance for Industry: Food-effect bioavailability and fed bioequivalence studies. 2002. http://www.fda.gov/ downloads/regulatoryinformation/guidances/ ucm126833.pdf. Accessed on November 26, 2013. [25] EMEA Guideline on the Investigation of Bioequivalence. 2010 http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. Accessed on March 10, 2014. [26] He YL, Flannery B, Campestrini J, Leon S, Zinny MA, Ligueros-Saylan M, Jarugula V. Effect of food on the pharmacokinetics of a vildagliptin/ metformin (50/1000 mg) fixed-dose combination tablet in healthy volunteers. Curr Med Res Opin. 2008; 24: 1703-1709. CrossRef PubMed [27] Karim A, Slater M, Bradford D, Schwartz L, Laurent A. Oral antidiabetic drugs: effect of food on absorption of pioglitazone and metformin from a
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Original ©2015 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP202233 e-pub: December 29, 2014
Effect of food on the pharmacokinetics of canagliflozin/metformin (150/1,000 mg) immediate-release fixed-dose combination tablet in healthy participants Joseph Murphy1, Shean-Sheng Wang1, Hans Stieltjes2, Ewa Wajs2, and Damayanthi Devineni1 1Janssen
Research & Development, LLC, Raritan, NJ, USA, and & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium
2Janssen Research
Key words food effect – canagliflozin – metformin – fixed-dose combination – pharmacokinetics – sodium-glucose co-transporter 2 inhibitor
Received August 12, 2013; accepted October 21, 2014 Correspondence to Dr. Damayanthi Devineni Janssen Research & Development, LLC, 920 Route 202, Raritan, NJ 08869, USA [email protected]
Abstract. Objective: To assess the effect of food on the pharmacokinetics (PK) of canagliflozin and metformin following administration of a canagliflozin/metformin (150/1,000 mg) immediate-release (IR) fixed-dose combination (FDC) tablet. Methods: A randomized, open-label, singlecenter, single-dose, 2-period, 2-sequence crossover study was conducted in healthy participants. Participants were randomized to 2 sequences of fasted and fed (or vice versa) administration of one 150/1,000 mg canagliflozin/metformin IR FDC, with 10 – 14 day washout between treatments. PK parameters (AUC, Cmax, tmax, t1/2) were assessed for canagliflozin and metformin. Safety was evaluated. Results: When comparing the IR FDC tablet administered with and without food, PK parameters of canagliflozin were bioequivalent as the 90% confidence intervals (CIs) for log-transformed AUClast, AUC∞, and Cmax were within the bioequivalence limits of 80 – 125%. For metformin, overall exposure was similar under fed and fasted conditions as geometric mean ratios for AUC and associated 90% CI were contained within the bioequivalence limits, but geometric mean Cmax decreased by 16% in the fed compared to fasted state. Both treatments were well tolerated with similar adverse events and most common were gastrointestinal events, generally attributed to metformin. Conclusions: Food did not affect canagliflozin bioavailability parameters (Cmax and AUCs) or AUCs of metformin. The Cmax of metformin was decreased by 16%, which is not considered clinically meaningful. The canagliflozin/ metformin FDC tablet is recommended to be taken with meals to reduce the symptoms of gastrointestinal intolerability associated with metformin.
Introduction Oral antidiabetic combination therapy is emerging as the standard of care in long-term clinical management of type 2 diabetes mellitus (T2DM) in adults. Canagliflozin (Invokana™ ) is a new orally bioavailable selective inhibitor of sodium-glucose co-transporter 2 (SGLT2) that acts on proximal renal tubules to decrease renal glucose reabsorption and increase urinary glucose excretion, thereby decreasing plasma glucose levels in patients with hyperglycemia [1, 2]. Canagliflozin is approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM in numerous countries worldwide. The recommended dose of canagliflozin is 100 or 300 mg once daily [3, 4, 5, 6, 7]. For many decades, metformin has been the recommended first-line oral antidiabetic therapy in management of T2DM in patients whose hyperglycemia is not adequately controlled by diet alone [8]. Metformin primarily acts by decreasing hepatic gluconeogenesis and improving insulin sensitivity [9]. Metformin can be prescribed up to maximum daily doses of 2,500 mg in adults and is available as immediate-release (IR) tablets of metformin hydrochloride (HCl) at 500, 850, and 1,000 mg dose strengths [10, 11]. Based on the position statement by the American Diabetes Association and the European Association for the Study of Diabetes, for patients who are inadequately controlled with metformin monotherapy, additional antihyperglycemic agents with complementary mechanisms of action may be prescribed [8]. Canagliflozin has a unique insulin-inde-
Effect of food on the pharmacokinetics of canagliflozin/metformin
pendent mechanism of action [12] that may provide new treatment approaches for T2DM as add on combination with metformin. In clinical studies of patients with T2DM, canagliflozin 300 mg was administered as addon to background metformin or combination of metformin plus sulfonylurea, and demonstrated significant reduction in HbA1c from baseline to week 52 compared with respective active controls, glimepiride, and sitagliptin [13, 14, 15, 16]. Canagliflozin 100 and 300 mg improved glycemic control, reduced body weight and was generally well tolerated in patients with T2DM inadequately controlled on metformin plus pioglitazone over 52 weeks [17]. A fixed-dose combination (FDC) tablet containing both canagliflozin and metformin in a single IR tablet offers improved patient compliance by simplifying administration and reducing pill burden. The canagliflozin (50 and 150 mg)/metformin (850 and 1,000 mg) IR FDC tablet has received regulatory approval in the European Union and the United States (50 and 150 mg/500 and 1,000 mg) for the treatment of adults with T2DM to improve glycemic control in patients not adequately controlled on their maximally tolerated doses of metformin alone or combined with other glucose lowering medicinal products including insulin, and patients already treated with combination of canagliflozin and metformin as separate IR tablets [18]. Canagliflozin/metformin IR FDC tablets or co-administration of single component IR tablets were established to be bioequivalent and are considered therapeutically equivalent and interchangeable in clinical practice [19]. Administration of food with a drug may alter the drug’s pharmacokinetics (PK) due to changes in drug absorption and metabolism resulting from possible factors such as delay in gastric emptying, changes in gastrointestinal fluid pH, and stimulation of bile flow in the gut affecting drug solubility and rate of dissolution [20, 21]. In addition, food-drug interaction may affect drug clearance and metabolism through changes in the splanchnic blood flow and plasma protein binding and modulation of drug-metabolizing enzymes [22, 23]. Therefore, it is important to establish the impact of food on the oral bioavailability and PK of the canagliflozin/ metformin IR FDC tablet in order to understand the clinical relevance of food-induced
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changes on both canagliflozin and metformin efficacy and tolerability and determine optimum timing of drug administration relative to meal times. The present clinical study investigated the effect of concomitant intake of a standardized, high-fat breakfast relative to fasted state on the PK of the canagliflozin/ metformin IR FDC tablet. The highest strength of the FDC tablet manufactured at 150/1,000 mg for twice a day dosing was investigated in accordance with US FDA and EMA guidelines on food-effect bioavailability and fed bioequivalence studies [24, 25], and similarly designed food effect studies on other antidiabetic agents formulated as FDC with metformin [26, 27, 28].
Methods Study population Men and women aged 18 – 55 years, who were considered healthy based on medical history, physical examination, and clinical laboratory evaluations, were enrolled in this study. Participants had a body mass index (BMI) of 18 – 30 kg/m2, body weight ≥ 50 kg, and blood pressure between 90 and 140 mmHg. Pregnant or breast feeding women were excluded. Individuals with a history of smoking, drug or alcohol abuse, and known allergy to the study drug were excluded. Participants refrained from taking any over-the-counter or prescription medications (with the exception of paracetamol, oral contraceptives, and hormonal replacement therapy) for at least 14 days prior to first drug administration and throughout the study. The protocol for the study was approved by an Institutional Review Board at the study site (Quintiles Phase One Services, KS, USA) and the study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki and in accordance with International Conference on Harmonisation Good Clinical Practice guidelines, applicable regulatory requirements, and in compliance with the protocol. All participants provided written informed consent to participate in the study.
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Study design and treatments This was a randomized, open-label, single-center, single-dose, 2-period, 2-sequence crossover study (NCT01459094) consisting of 3 phases: a screening phase of up to 28 days (day –22 through day –2); an open-label treatment phase of up to 19 days (including a washout period of 10- to 14-days between day 1 of each treatment period), and a follow-up phase of up to 10 days after day 4 of period 2 or at early withdrawal. On day 1 of treatment period 1, all participants were randomized (1 : 1) to receive either reference treatment A (fasting conditions) in period 1, followed by test treatment B (fed condition) in period 2 (sequence AB) or vice versa (BA). Participants received a single canagliflozin/metformin IR FDC tablet containing 150 mg of canagliflozin and 1,000 mg of metformin at each treatment period. Following an overnight fast of at least 10 hours, study drug administration occurred at approximately the same time each morning. Participants in reference treatment A (fasted) received study drug without food and participants in test treatment B (fed) received study drug 30 minutes after starting a standardized high-fat breakfast which participants were to complete during the allotted time. Study drug was administered with 240 mL of noncarbonated water. No food was allowed for at least 4 hours postdose in either treatment and water was withheld 1 hour before and after study drug administration with the exception of the water given with study medication.
Pharmacokinetic evaluations Sample collection A blood sample collection period of 72 hours for canagliflozin and 24 hours for metformin were used given the estimated 13- to 23-hour elimination half-life of canagliflozin and the estimated 6-hour half-life of metformin. Venous blood samples (2 mL for canagliflozin and 2 mL for metformin) for determination of canagliflozin and metformin plasma concentrations were collected in glass or plastic K2EDTA-containing tubes (e.g., Vacutainer®) at predose, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36 (canagliflozin only), 48 (canagliflozin only), and 72 (cana-
gliflozin only) hours postdose on day 1 of each treatment period. The samples were centrifuged at room temperature (10 minutes at 1,300 g) to obtain plasma. All plasma samples were stored at or below –20 °C until transferred to a bioanalytical facility. Analytical methods Plasma canagliflozin concentrations were determined with 13C6-canagliflozin as internal standard (IS) using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method at PRA International (Assen, The Netherlands). The HPLC system consisted of a Shimadzu LC-10Advp pump with Shimadzu SIL-HTC autosampler (Shimadzu Corporation, Kyoto, Japan). An API4000 mass spectrometer with a TurboIonsprayTM Interface (AB SCIEX, MA, USA) in the positive ion mode was used for MS determination. Multiple reaction monitoring (MRM) transitions were m/z 462.1 → 267.0 and 468.1 → 273.0 for canagliflozin and IS, respectively. The method for canagliflozin plasma determination used a liquid-liquid extraction with tert-butylmethylether, followed by chromatography with 30% ammonium acetate (0.01 M) and 70% methanol as the mobile phase. The flow rate was 0.25 mL/min on a Waters XBridgeTM C18 column (5 cm × 2.1 mm, 3.5-µm particle size), kept at 30 °C. The validated quantification range was 5.0 – 5,000 ng/mL. Plasma metformin concentrations were determined with 2H6-metformin as IS. The same LC-MS/MS system as for the canagliflozin assay was used, but with an API3000 mass spectrometer, in the positive ion mode. MRM transitions were m/z 130.1 → 70.9 and 136.0 → 77.0 for metformin and metformin IS, respectively. The sample preparation consisted of a protein precipitation with acidic (formic acid) acetonitrile, followed by gradient ion-pair chromatography with 0.02 M hexafluorobutyric acid in 0.01 M ammonium acetate (A) and acetonitrile (B), from at 5% to 27.5% B in 3 minutes. The flow rate was 0.3 mL/min over a Waters XBridgeTM Shield RP18 column (5 cm × 2.1 mm, 3.5-µm particle size), kept at 40 °C. The validated quantification range was 5.0 – 2,500 ng/mL. The validation was performed according to FDA guidance for bioanalysis [29,
Effect of food on the pharmacokinetics of canagliflozin/metformin
30]. This included within- and between-run precision and accuracy, selectivity, matrix effect, recovery, incurred sample reproducibility and stability (blood, plasma, processed sample). All validation results were within predefined acceptance criteria. The storage period between sample collection and analysis was covered by the available long-term stability data for the analytes in the presence of the other analyte (for canagliflozin 762 days and for metformin 190 days at –20 °C). Pharmacokinetic analyses The following plasma PK parameters were determined for canagliflozin and metformin based on the individual participant plasma concentration-time data, using actual sampling times via non-compartmental methods using validated WinNonlin® software Version 5.2.1 (Pharsight Corporation, Mountain View, CA, USA): maximum observed plasma concentration (Cmax), time to reach maximum observed plasma concentration (tmax), terminal elimination half-life (t1/2) associated with the terminal slope (λz) of the semilogarithmic drug concentrationtime curve, calculated as 0.693/λz, area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast), area under the plasma concentration-time curve from time 0 to infinite time (AUC∞), calculated as the sum of AUClast and Clast/λz, in which Clast is the last observed quantifiable concentration and λz is the terminal slope of the semilogarithmic drug concentration-time curve.
Safety assessments Safety evaluations were based upon the type, incidence, and severity of treatmentemergent adverse events (TEAEs) reported throughout the study, and on clinical laboratory tests, vital sign measurements, physical examinations, and 12-lead electrocardiograms (ECG) assessed at pre-defined time points.
Statistical analyses Sample size The intra-participant coefficient of variation (CV) of AUCs and Cmax were estimated
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to be no more than 10% and 25%, respectively for canagliflozin, and no more than 20% for both AUCs and Cmax for metformin. Using an intra-participant CV of 10% and 25% for AUCs and Cmax for canagliflozin, and the simple size of 20 participants to complete the study, the ratio of geometric mean AUC and Cmax of canagliflozin with food to without food would fall within 95 – 106% and 87 – 115%, respectively, of the true value with 90% confidence. Similarly, using an estimated intra-participant CV of 20% for AUCs and Cmax, respectively for metformin, a sample size of 20 participants would be sufficient for the ratio of geometric mean AUCs and Cmax of metformin with food to without food to fall within 90% to 112% of the true value with 90% confidence. Planned enrollment was 24 participants to ensure 20 participants completed the study. Statistical comparison The primary PK parameters of interest for the statistical analysis were the log-transformed canagliflozin and metformin AUC∞, AUClast and Cmax values. A mixed-effects modelling (Proc Mixed procedure in SAS (SAS Institute, version 9.2, Cary, NC, USA)) appropriate for crossover design was fitted to the PK parameter of interest. The model included treatment (fed and fasted), period (periods 1 and 2), and treatment sequence (treatment sequences 1 and 2) as fixed effects and participant as a random effect was applied to estimate the least squares mean of each treatments and the corresponding intra-participant variance. Using these estimated least squares means and intra-participant variances, the 90% confidence interval (CI) for the difference in means on a log scale between treatment A and B were constructed. The limits of the CI were retransformed using antilogarithms to obtain the 90% CI for the ratios of the mean values for AUCs and Cmax of the test (fed) to reference (fasted) formulation. Only data from participants who completed the study were included in the statistical analysis. If 1 of the PK parameters of interest was not estimable for a given participant in 1 or more periods, then that participant’s data was not to be included in the statistical analysis of that particular parameter.
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Table 1. Summary statistics for geometric means and ratio of geometric means with corresponding 90% confidence intervals (CIs) for canagliflozin pharmacokinetic parameters following administration of single dose of canagliflozin/metformin IR FDC tablet (150/1,000 mg) in the fed and fasted state. Parameter
Geometric mean Fed (test) Fasted (ref) n = 24 n = 24 Cmax (ng/mL) 1,325 1,463 12,612 11,307 AUClast (ng×h/mL) 13,117 11,650 AUC∞ (ng×h/mL)a 3.5 (1.0 – 6.0) 1.5 (1.0 – 5.0) tmax (h)b 21.5 (7.48) 19.8 (6.30) t1/2 (h)c
Geometric mean ratio (%) (90% CI) (test/reference) 90.6 (80.7 – 101.7) 111.5 (107.2 – 116.0) 112.6 (108.0 – 117.3)
IR = immediate-release; FDC = fixed dose combination; AUClast = area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration; AUC∞ = area under the plasma concentration-time curve from time 0 to infinite time; CI = confidence interval; Cmax = maximum observed plasma concentration; tmax = time to reach Cmax; t1/2 = elimination half-life. an = 22; b tmax, reported as median (range); ct1/2, reported as arithmetic mean (SD); n = 23.
TEAEs were summarized by treatment within each body system and for each preferred term. Results of clinical laboratory tests, vital signs, and ECG parameters were summarized using descriptive statistics.
Results Study disposition and demographics A total of 24 participants (15 men, 9 women) were enrolled and all completed both fasted and fed treatment sequences. Participants were Black or African American (14, 58%), White (8; 33%), or American Indian or Alaska Native (2, 8%). Mean (SD) age was 31.7 (10.9) years, weight 76.3 (9.0) kg, and BMI 25.4 (2.5) kg/m2. The demo-
graphic and baseline characteristics of participants in the 2 treatment sequence groups were comparable in terms of the mean age, weight, BMI and number of men and women.
Pharmacokinetic analyses Canagliflozin Following administration of the canagliflozin/metformin FDC IR tablet under fed and fasting conditions, the PK parameters for canagliflozin were similar for both treatments (Table 1). The fed-to-fasted geometric mean ratios (GMRs) and the corresponding 90% CI for AUClast, AUC∞, and Cmax were 111.5% (CI: 107.2, 116.0), 112.6% (CI: 108.0, 117.3), and 90.6% (CI: 80.7, 101.7), respectively. The 90% CIs for the GMRs of canagliflozin treatment under fed vs. fasted conditions were contained within the bioequivalence limits of 80% to 125% for Cmax and AUCs. The mean plasma canagliflozin concentrations following oral administration of the canagliflozin/metformin FDC tablet with or without food are shown in Figure 1A. The median tmax of canagliflozin was delayed following administration under fed conditions compared with fasted conditions (3.5 and 1.5 hours, respectively). However, a prolongation in tmax without a decrease in overall systemic exposure (AUC) is not considered clinically relevant. Mean apparent t1/2 values of canagliflozin were 19.8 hours and 21.5 hours in participants under fasting and fed conditions, respectively.
Figure 1. Mean (+SD) plasma concentration-time profiles for (A) canagliflozin and (B) metformin following administration of canagliflozin/metformin IR FDC tablet in the fed and fasted state. Conc = concentration; SD = standard deviation.
Effect of food on the pharmacokinetics of canagliflozin/metformin
Table 2. Summary statistics for geometric means and ratio of geometric means with corresponding 90% CI for metformin pharmacokinetic parameters following administration of single dose of canagliflozin/metformin IR FDC Tablet (150/1,000 mg) in the fed and fasted state. Parameter
Geometric mean Fed (test) Fasted (ref) n = 24 n = 24 Cmax (ng/mL) 1,373 1,643 10,908 10,951 AUClast (ng×h/mL) 11,222 11,228 AUC∞ (ng×h/mL) 3.0 (1.5 – 5.0) 2.0 (1.0 – 3.0) tmax (h)a 4.3 (0.41) 4.5 (0.71) t1/2 (h)b
Geometric mean ratio (%) (90% CI) (test/reference) 83.6 (77.2 – 90.5) 99.6 (91.9 – 108.0) 100.0 (92.3 – 108.2)
IR = immediate-release; FDC = fixed dose combination; AUClast = area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration; AUC∞ = area under the plasma concentration-time curve from time 0 to infinite time; CI = confidence interval; Cmax = maximum observed plasma concentration; tmax = time to reach Cmax; t1/2 = terminal elimination half-life. a tmax = reported as median (range), bt1/2 = reported as arithmetic mean (SD).
Metformin The PK parameters for metformin demonstrated that the metformin exposure was similar for the FDC tablet under fed and fasted condition (Table 2). The GMRs for metformin AUClast and AUC∞ and the associated 90% CI were 99.6% (CI: 91.9, 108.0) and 112.6% (CI: 108.0 – 117.3), respectively, and were contained within the bioequivalence limits of 80 – 125% indicating that AUCs for metformin were not affected by food. However, the geometric mean Cmax of metformin decreased by 16% in the fed as compared to the fasted state and did not meet the bioequivalence criteria (GMR of Cmax: 83.6%; 90% CI: 77.2, 90.5) (Table 2). The absorption phase of plasma metformin concentrations-time profiles was lower following administration of the canagliflozin/metformin FDC tablet under fed as compared to the fasted state (Figure 1B). Median tmax was 2.0 hours following administration of the FDC tablet without food (range 1.0 – 3.0 hours) and 3.0 hours after coadministration with food (range 1.5 – 5.0 hours). Mean apparent t1/2 of metformin was 4.46 hours under fasting conditions and 4.32 hours under fed conditions.
Safety and tolerability There were no deaths, other serious adverse events, or discontinuations due to adverse events. The incidence of TEAEs was
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the same after fasted and fed administration of the FDC tablet (n = 16; 66.7% in each treatment). The incidence of different TEAEs within each system organ class was comparable after both fasted and fed treatment. The most commonly reported TEAEs following both treatments were gastrointestinal disorders (14/24 (58.3%)). Overall, the most common TEAE was diarrhea, with the same incidence in both treatments (8/24 (33.3%)). The majority of gastrointestinal adverse events were judged by the investigator as very likely related to the administered treatment. There were no hypoglycemic events reported. There were no treatment-related changes from baseline in mean vital sign measurements, ECG parameters, or physical examinations, or in any of the routine clinical laboratory safety tests (i.e., hematology, chemistry, and urinalysis) that were considered to be clinically significant. Overall, no new, unexpected, or unusual safety signals were noted.
Discussion The present study evaluated the effect of food on the PK of the canagliflozin/metformin FDC IR tablet (150/1,000 mg) in healthy participants. For the fed condition, a single dose of the FDC tablet was administered 30 minutes after the start of a standardized, high-fat breakfast as compared to the fasted condition. Administration of the canagliflozin/metformin FDC tablet with food did not meaningfully alter the PK parameters of canagliflozin relative to the fasted state as the 90% CIs for GMR’s for AUClast, AUC∞, and Cmax were contained within the bioequivalence limits of 80 – 125%. The median tmax of canagliflozin was slightly delayed under fed as compared to fasted condition consistent with delay in rate of gastric emptying following ingestion of a high-fat meal and is not considered clinically relevant since its overall systemic exposure was unchanged. These results are consistent with the clinical findings of a separate food effect study that demonstrated oral bioavailability of single component 300 mg canagliflozin IR tablet was not impacted by ingestion of food [31]. This also indicates that the IR FDC formulation of canagliflozin with metformin did
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not produce a different food related change in its bioavailability than observed from the single agent canagliflozin IR tablet. The extent of absorption (AUCs) of metformin was similar between fasted and fed conditions as the 90% CIs for GMRs of metformin AUCs were within the bioequivalence limits of 80 – 125%. The mean Cmax of metformin was decreased by 16% and its median tmax delayed by about 1 hour following administration under fed conditions as compared to fasted condition. However, the small decrease in metformin Cmax under fed condition is not considered clinically important as AUC rather than Cmax is considered to be responsible for metformin antihyperglycemic effect [32]. This finding is consistent with results of other clinical studies in which co-administration with food of a metformin HCl IR tablet alone [33], or as an IR FDC tablet with other antidiabetic agents [26, 27, 28], resulted in reduced Cmax by 15 – 39% and delayed tmax by 0.5 – 1.5 hours. In one study, AUC of 850 mg metformin IR tablet decreased by ~ 25% [33]. Administration of a single dose of canagliflozin/metformin (150/1,000 mg) IR FDC tablet to healthy participants was well tolerated. The most commonly reported TEAEs were gastrointestinal disorders with similar incidence in the fed and fasted states and largely characteristic of the metformin component of the FDC tablet. Although the effect of food induced changes on the PK of canagliflozin/metformin FDC IR tablet was not clinically relevant, as metformin HCl IR is recommended to be administered with a meal to reduce the incidence of gastrointestinal side effects, it is also recommended that canagliflozin/metformin (150/1,000 mg) IR FDC tablet be taken with a meal to reduce gastrointestinal intolerability associated with metformin [10, 11].
and a small decrease in mean Cmax of metformin under the fed condition is not considered clinically relevant. Metformin HCl IR is recommended to be administered with a meal to reduce the incidence of gastrointestinal side effects, and therefore the intended mode of administration for the canagliflozin/metformin IR FDC tablet is similarly with meals.
Acknowledgments We acknowledge Dr. Bradford Challis (Janssen Research & Development, LLC) for providing writing assistance for the development of this manuscript. We thank Nicole Vaccaro (Janssen Research & Development, LLC) for generating figures. We thank the study participants, without whom the study would never have been accomplished, and the investigator Dr. Eleanor Lisbon (United States) for her participation in the study.
Conflict of interest The study presented in this report was supported by Janssen Research & Development, LLC. All authors are employees of Janssen Research & Development, LLC or of Janssen Research & Development, A division of Janssen Pharmaceutica NV, and hold stock in the company.
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Conclusion Administration of the canagliflozin/metformin (150/1,000 mg) IR FDC tablet with food did not alter to a clinically relevant extent the PK parameters of canagliflozin relative to the fasted state. Food did not affect the extent of absorption (AUCs) of metformin
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