Clinical Therapeutics/Volume ], Number ], 2015
Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects Xia Chen, MD1; Pei Hu, MD1; Nicole Vaccaro, BS2; David Polidori, PhD2; Christopher R. Curtin, BS3; Hans Stieltjes, MSc4; Sue Sha, MD, PhD3; Sveta Weiner, MS3; and Damayanthi Devineni, PhD3 1
Phase I Unit of Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China; 2Janssen Research & Development, LLC, San Diego, California; 3Janssen Research & Development, LLC, Raritan, New Jersey; and 4Janssen Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium
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 (AUC0–1, 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 AUC0–1 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 24hour increased urinary glucose excretion (33.8 and
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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. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: canagliflozin, pharmacodynamics, pharmacokinetics, safety, sodium-glucose cotransporter 2 inhibitor.
INTRODUCTION Type 2 diabetes mellitus (T2DM) is a growing concern, accounting for 490% of the diagnosed cases of diabetes worldwide.1 In China, the diabetes epidemic is accelerating at an alarming rate, with 92.4 million adults estimated to be diabetic.2 Although many Accepted for publication April 30, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.04.015 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics medications are available for the management of this disease, the use of antihyperglycemic agents is often limited by weight gain, episodes of hypoglycemia, edema, potential cardiovascular disorders, and/or adverse gastrointestinal effects.3,4 Canagliflozin,* a sodium–glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.5–7 It acts on the proximal renal tubules, thereby reducing glucose reabsorption and increasing urinary glucose excretion (UGE). This novel insulin-independent approach lowers plasma glucose (PG) and increases caloric loss (4 kcal/g of glucose).8,9 The recommended starting dose of canagliflozin is 100 mg/d, to be administered before the first meal of the day; in patients with an estimated glomerular filtration rate (eGFR) of Z60 mL/min/1.73 m2 who require additional glycemic control, the dosage may be increased to 300 mg/d.9–12 Canagliflozin is mostly metabolized through the O‐glucuronidation metabolic elimination pathway, and the 2 major metabolites are the inactive M5 and M7 O‐glucuronide conjugates of the unchanged drug.13,14 The pharmacokinetic (PK) characteristics of canagliflozin have been evaluated after single and multiple oral dose administration in healthy subjects and in patients with T2DM in Western populations.13–15 After oral administration in healthy subjects and in patients with T2DM, canagliflozin was rapidly absorbed, with the median Tmax occurring 1 to 2 hours postdose.16 In healthy subjects, the mean AUC of canagliflozin increased in a dose-dependent manner across a wide range of doses (25–1600 mg), whereas Cmax increased in a dose-proportional manner from 50 to 300 mg16,17 and even up to 1200 mg (unpublished data). In patients with T2DM, the Cmax and AUC of canagliflozin also increased in a linear manner over the dose range of 50 to 300 mg.13 Mean terminal t½ ranged from 10.6 to 13.1 hours with the 100- and 300-mg doses. No dose-related clinical adverse drug reactions were reported for single doses up to 1600 mg of canagliflozin in healthy subjects (unpublished data). The highest multiple-dose canagliflozin regimen evaluated in clinical studies was 300 mg BID, which was used both in a 4-week dose-ranging study in patients Trademark: Invokanas (Janssen Pharmaceuticals, Inc, Titusville, New Jersey).
*
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with T2DM18 and in a 12-week, Phase II dose-ranging study in patients with T2DM.7 It was found to be safe and generally well tolerated in both studies. Ethnicity is one factor that may account for the observed differences in both PK and pharmacodynamics (PD) of drugs, resulting in variability in response to drug therapy.19 The dose- and weightnormalized PK parameters of canagliflozin demonstrated no apparent differences in canagliflozin exposure among healthy Western, Indian, and Japanese subjects, as well as between Western and Japanese patients with T2DM.20 Moreover, after canagliflozin treatment at comparable doses, the PD parameters (UGE, both 24-hour and fasting PG, and renal threshold for glucose excretion [RTG]) exhibited a similar pattern of dose-dependent changes in Western,13–15 Korean,21 and Japanese patients with T2DM.22,23 To further explore potential interethnic differences in the PK and PD characteristics of canagliflozin, a Phase I study was conducted in healthy Chinese subjects. The doses selected for the present study (100 and 300 mg) were previously evaluated in healthy Western subjects and were found to be generally well tolerated.14,15 In addition, these doses were shown to be efficacious in global Phase III trials in patients with T2DM.9,24–26
SUBJECTS AND METHODS Study Population Fifteen healthy Chinese men and women, aged between 18 and 55 years, with a body mass index between 18 and 28 kg/m2 and weight Z50 kg, were enrolled. Participants were excluded from the study if there was evidence of the following: any clinically significant medical illness, history of smoking or drug or alcohol abuse, or known allergy to canagliflozin. Pregnant or breastfeeding women were also excluded. Subjects were prohibited from taking any over-thecounter or prescribed medications except acetaminophen for at least 14 days before study initiation and throughout the study. Women on hormone replacement therapy or contraceptives continued the same medication throughout the study. The study protocol was approved by the local independent ethics committee and was conducted in accordance with the ethical principles originating in the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice Guideline, and applicable regulatory requirements and in
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X. Chen et al. compliance with the protocol. All participants provided written informed consent to participate in the study.
sample were stored at 201C or lower until transferred to a bioanalytical facility.
PK and PD Analytical Methods Study Design and Treatment This single-center, double-blind, randomized, placebo-controlled, single-dose, 3-way crossover study consisted of 3 phases: the screening phase (3 weeks), a treatment phase (including three 5-day treatment periods and 2 interperiod washout sessions of at least 10 days), and the safety follow-up phase (7–10 days) after completion of the third treatment period. Eligible participants were randomized to 1 of 3 treatment sequence groups (ABC, BCA, or CAB) by using a computer-generated randomization schedule. Subjects received canagliflozin 100 mg (treatment A), canagliflozin 300 mg (treatment B), and placebo (treatment C) based on their randomized treatment sequence group. The study drugs were administered 10 minutes before a standardized breakfast on all dosing days.
Clinical Evaluations PK Sample Collection Blood samples (3 mL) for the bioassays of canagliflozin and its metabolites M7 and M5 were collected into dipotassium EDTA tubes at predose and at 0.5, 1, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose during each treatment period. The samples were cool-centrifuged (10 minutes at 1300 g), and the obtained plasma was stored at 201C or lower. Urine samples for the measurement of canagliflozin and M7 and M5 concentrations were collected in the following time intervals: 0 to 4, 4 to 10, 10 to 13, 13 to 24, and 24 to 48 hours postdose during each treatment period. The total volume of the urine over each time interval was recorded, and an aliquot of each urine sample was stored at 201C or lower until further analyses were conducted.
PD Sample Collection PG was assessed by using blood samples (2 mL) obtained at predose as well as 10 minutes and 0.5, 1, 1.5, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 11, 11.5, 12, 13, 14, 16, and 24 hours postdose during each treatment period. Urine samples (10 mL) were collected over the predefined intervals of 0 to 4, 4 to 10, 10 to 13, 13 to 24, and 24 to 48 hours postdose for determination of UGE. All plasma samples and an aliquot of each urine
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The concentrations of canagliflozin and its metabolites in plasma and urine samples were determined by using previously described,13 validated (plasma) or qualified (urine) specific, sensitive LC-MS/MS methods at Frontage Laboratories (Shanghai) Co, Ltd (Shanghai, China). In brief, the methods consisted of a liquid– liquid extraction with tertiary butyl methyl ether, followed by LC-MS/MS analysis using isocratic reversed-phase chromatography on a C18 column. The bioanalytical methods for canagliflozin and its metabolites M7 and M5 in plasma had a calibration range of 5 to 10,000 ng/mL. The calibration range in urine was 25 to 10,000 ng/mL for canagliflozin and 100 to 100,000 ng/mL for M7 and M5. All bioanalytical runs met the predefined acceptance criteria. Plasma and urine samples were analyzed to determine concentrations of glucose by using conventional laboratory testing at Covance Central Laboratory Services SA (Geneva, Switzerland).
PK and PD Analyses The plasma PK parameters were determined for canagliflozin, M7, and M5 based on individual plasma concentration–time profiles, using actual sampling times, according to noncompartmental analysis with validated WinNonlin version 5.3 software (Pharsight Corporation, Mountainview, California). Key PK parameters included: Cmax, Tmax, t½, AUC0–1 (calculated as the sum of AUC0–last and C0–last/λz [terminal slope]), CL/F (for the parent compound only), the metabolite to parent ratio for Cmax (M/P Cmax ratio, metabolites only), and the metabolite to parent ratio for AUC0–1 (M/P AUC0–1 ratio, metabolites only). The following urine PK parameters for canagliflozin, M7, and M5 were determined: cumulative amount excreted in the urine, expressed as a percentage of the administered dose, corrected for molecular weight only for metabolites, and renal clearance (CLR). Key PD parameters included RTG, calculated for each scheduled urine collection interval and for each 24-hour urine collection period; UGE, defined as the amount of glucose excreted into the urine over the entire urine collection interval (0–24 hours) and
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Clinical Therapeutics calculated as the sum of all the UGEt1–t2 values from 0 to 24 hours postdose; and mean plasma glucose (MPG), calculated as the MPG concentration from time 0 to 24 hours after dosing. The values of MPG0–24 were determined from the measured PG profiles by calculating the AUC (using the linear trapezoidal rule) from 0 to 24 hours and dividing by 24 hours (calculations performed by using WinNonlin version 5.2.1; Pharsight Corporation). Postprandial mean incremental PG concentrations during the 0 to 2 hour (MΔPG0–2) and the 0 to 4 hour (MΔPG0–4) intervals were calculated as the positive incremental areas under the PG profile and above the premeal PG concentration. Values of RTG were calculated during each collection interval by using the measured PG profiles, UGE, and eGFR as described previously.14,27 Because the commonly used Modification of Diet in Renal Disease (MDRD) formula for eGFR has not yet been validated in Chinese subjects, the RTG values were calculated by using 2 separate estimates for GFR: eGFR from the MDRD formula (denoted as RTG: MDRD) and measured 24-hour creatinine clearance (MCrCl) (denoted as RTG: MCrCl).28,29 The 24-hour mean RTG values were calculated as the weighted mean of the RTG values obtained over individual urine collection intervals (the RTG value over each interval was multiplied by the duration of the interval, and the sum of these values was divided by 24 hours).
Safety Assessments Safety evaluations included assessments of treatmentemergent adverse events (TEAEs), changes in routine clinical laboratory test results, vital sign measurements (blood pressure, pulse rate, and body temperature), physical examinations, 12-lead ECGs, and documentation of hypoglycemic episodes at predefined time points.
Statistical Analysis Sample Size Based on data from earlier Phase I studies of canagliflozin in healthy subjects, the intersubject % CV for Cmax and AUC of canagliflozin after singledose administration was estimated to be r30%. Based on an estimated intersubject %CV of r30% for Cmax and AUC of canagliflozin after single-dose administration, a sample size of 12 subjects was considered sufficient for the point estimate of
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geometric means of Cmax and AUC0–1 to fall within 83% and 121% of the true value with 95% confidence. Based on an estimated intersubject %CV of 35% for 24-hour mean RTG, a sample size of 12 completed subjects was considered sufficient for the point estimate of the geometric 24-hour mean RTG for each canagliflozin dose to fall within 80% and 125% of the true value with 95% confidence. Based on an intersubject SD of 8 g for UGE0–24, a sample size of 12 completed subjects was considered sufficient for the point estimate of the arithmetic mean UGE0–24 for each canagliflozin dose to be within ⫾5.1 g of the true value with 95% confidence. Fifteen participants were enrolled to allow for potential dropouts.
PK, PD, and Safety Profile All participants who completed the study were included in the PK and PD analyses. All participants who were randomly assigned to treatment and received at least 1 dose of the study drug were included in the safety and tolerability analyses. The PK, PD, and safety findings were summarized descriptively.
RESULTS Patient Disposition and Demographic Characteristics This study was conducted at a single center in Beijing, China, from July 2012 to August 2012. Fifteen healthy Chinese subjects (9 men, 6 women) were enrolled; all subjects received the study drug, and 14 (93%) completed the study. One female subject receiving 100 mg of canagliflozin withdrew consent prematurely for personal reasons after dosing on day 1 of period 1. Baseline characteristics of subjects are summarized in Table I.
Pharmacokinetics After single-dose administration of canagliflozin, plasma canagliflozin concentrations increased rapidly at both dose levels (100 and 300 mg), with median Tmax values of 1 hour (Figure 1). Mean Cmax and AUC0–1 values for canagliflozin increased in a dosedependent manner. Mean apparent t½ values were 16.0 hours and appeared to be independent of dose in this study. Mean CL/F and CLR were similar between the 2 doses (CL/F [L/h], 9.78 [1.84] and 9.26 [1.99] for 100 mg and 300 mg, respectively; CLR [L/h], 0.0514 [0.0187] and 0.0472 [0.00704] for 100 mg and 300 mg). Less
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X. Chen et al. than 1% of the administered dose was excreted in the urine as canagliflozin over the 48-hour urine collection period after a single dose (Table II). The plasma concentrations of M7 and M5 also increased rapidly after single-dose administration of 100- and 300-mg canagliflozin. Median Tmax values were 2 hours (range, 1.5–6 hours for 100 mg; 1.5–3 hours for 300 mg) and 3.5 hours (range, 2–4 hours for 100 mg; 1.5–4 hours for 300 mg) for M7 and M5, respectively (Figure 1). Mean terminal t½ values were 15 hours for both M7 and M5. With the investigated doses studied, 17% of the administered dose was recovered as M7 and 9% was recovered as M5 in the urine over the 48-hour period after single-dose canagliflozin administration. The mean M7 and M5 metabolite to parent (M/P) molar ratios (corrected for differences in molecular weights) for Cmax and AUC0–1 were similar between the 2 doses (Table II).
Table I. Demographic and baseline characteristics (safety analysis set). Study Population (N ¼ 15)
Characteristic Age, y* Sex, no. (%) Female Male Weight, kg* Body mass index, kg/m2*,† eGFR, mL/min/1.73 m2*
29.5 (4.90) 6 9 63.0 22.0 103
(40) (60) (7.32) (2.08) (11.44)
eGFR ¼ estimated glomerular filtration rate. * Mean (SD). † Obtained by using the Modification of Diet in Renal Disease formula.
Plasma Canagliflozin (ng/mL)
10,000 Canagliflozin 100 mg (n=14) Canaliflozin 300 mg (n=14) 1000
100
10 12
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48 36 Time (h)
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72
10,000
10,000
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1000
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M7 (ng/mL)
0
100
100
10
10 0
12
24
48 36 Time (h)
60
72
0
12
24
48 36 Time (h)
60
72
Figure 1. Plasma concentration–time profiles of (A) canagliflozin, (B) M7, and (C) M5 after administration of canagliflozin in healthy Chinese subjects.
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5
6
517 (148) 3.50 (2.00–4.00) 8006 (2502) 14.2 (3.21) 8.78 (2.94) — — 0.328 (0.08) 0.564 (0.17) 2155 (671) 2.00 (1.50–3.00) 26,302 (6381) 15.5 (4.25) 17.0 (3.39) — — 0.387 (0.11) 0.598 (0.20) 745 (265) 2.00 (1.50–6.00) 9050 (2502) 15.1 (3.62) 17.5 (5.23) — — 0.474 (0.15) 0.651 (0.22) 1178 (291) 1.00 (1.00–3.00) 10,521 (1707) 16.0 (4.13) 0.496 (0.21) 9.78 (1.84) 0.0514 (0.02) — — Cmax, ng/mL Tmax, h* AUC0–1, ng h/mL t½, h Ae % dose CL/F, L/h CLR, L/h M/P Cmax ratio M/P AUC0–1 ratio
4113 (665) 1.25 (1.00–1.50) 33,583 (6100) 16.2 (4.79) 0.481 (0.12) 9.26 (1.99) 0.0472 (0.01) — —
100 mg (n ¼ 14) 300 mg (n ¼ 14) 100 mg (n ¼ 14) Parameter
Ae % dose ¼ total amount excreted into the urine during a 24-hour dosing interval (expressed as a percentage of the administered dose); CLR ¼ renal clearance; M/P AUC1 ratio ¼ metabolite to parent (M/P) ratio for AUC1 corrected for molecular weight; M/P Cmax ratio ¼ metabolite-to-parent (M/P) ratio for Cmax. * Median (range).
1553 (474) 3.00 (1.50–4.00) 25,269 (8859) 15.2 (4.38) 8.83 (2.47) — — 0.276 (0.07) 0.561 (0.19)
300 mg (n ¼14) 100 mg (n ¼ 14) 300 mg (n ¼ 14)
M5 M7 Canagliflozin
Table II. Mean (SD) pharmacokinetic parameters of canagliflozin and its metabolites after administration of canagliflozin in healthy Chinese subjects.
Clinical Therapeutics
Pharmacodynamics Canagliflozin altered UGE and 24-hour mean RTG in a dose-dependent manner. The mean UGE0–24 was 33.8 and 42.9 g with the canagliflozin 100- and 300-mg doses, respectively (Table III). RTG values could not be calculated for the subjects receiving placebo because they had virtually no UGE; commonly quoted values of RTG in healthy subjects are 180 to 200 mg/dL.14 Using eGFR according to the MDRD formula, canagliflozin 100 mg and 300 mg decreased the mean RTG: MDRD to 76 and 68 mg/dL, respectively. When using MCrCl for eGFR, mean RTG: MCrCl values of 68 and 61 mg/dL were obtained with 100 mg and 300 mg of canagliflozin. The 24-hour PG profile was generally unchanged by canagliflozin (Figure 2A), with the exception of a blunted peak glucose excursion observed postbreakfast with both doses of canagliflozin and a delayed rise in postbreakfast PG in subjects receiving canagliflozin 300 mg (Table III, Figure 2B).
Safety Profile Treatment with both doses of canagliflozin (100 and 300 mg) was generally well tolerated. No deaths, serious adverse events, discontinuation due to TEAEs, hypoglycemic events, or persistent TEAEs were reported during the study. The incidence of TEAEs was 33.3% (5 of 15) with canagliflozin 100 mg, 33.3% (5 of 15) with placebo, and 13.3% (2 of 15) with canagliflozin 300 mg. The most commonly reported (45% participants) TEAEs were increased levels of blood bilirubin (canagliflozin 100 mg, 1 [6.7%]; placebo, 1 [7.1%]), presence of white blood cells in urine (canagliflozin 100 mg, 1 [6.7%]; canagliflozin 300 mg, 1 [7.1%]), dizziness (canagliflozin 100 mg, 1 [6.7%]; placebo, 1 [7.1%]), and vulvovaginal pruritus (canagliflozin 100 mg, 2 [13.3%]). All reported AEs were mild in severity as assessed by the investigator. There were no clinically relevant changes in other laboratory findings, vital signs, physical examinations, or ECG parameters.
DISCUSSION This Phase I study evaluated the PK, PD, and safety profile of canagliflozin in healthy Chinese subjects. After oral administration, canagliflozin was rapidly absorbed, and the exposure of canagliflozin and its metabolites increased in a dose-dependent manner. The mean plasma Cmax and AUC0–1 were 14% Volume ] Number ]
X. Chen et al.
Table III. Mean (SD) pharmacodynamic parameters of canagliflozin after administration of canagliflozin in healthy Chinese subjects. Placebo (n ¼ 14)
Parameter 24-hour mean RTG: 24-hour mean RTG: UGE0–24, g MPG0–24, mg/dL MΔPG0–2, mg/dL MΔPG0–4, mg/dL
MDRD, MCrCl,
mg/dL mg/dL
— — 0.009 (0.01) 99.4 (6.56) 30.5 (17.60) 20.5 (12.50)
Canagliflozin 100 mg (n ¼ 14) 76.2 67.9 33.8 98.2 23.0 16.0
(8.65) (14.10) (10.40) (6.34) (10.60) (7.03)
Canagliflozin 300 mg (n ¼ 14) 67.4 60.7 42.9 96.9 15.5 14.2
(5.14) (9.58) (6.67) (4.64) (10.00) (9.37)
RTG ¼ renal threshold for glucose excretion; RTG: MDRD ¼ RTG calculated by using the Modification of Diet in Renal Disease formula; RTG: MCrCl ¼ RTG calculated by using measured 24-hour creatinine clearance; UGE ¼ urinary glucose excretion; MPG0–24 ¼ mean plasma glucose concentration defined as the AUC0–24 postdose divided by 24; MΔPG0–2 ¼ mean incremental plasma glucose concentration from 0 to 2 hours; MΔPG0–4 ¼ mean incremental plasma glucose concentration from 0 to 4 hours.
to 42% and 57% to 62% higher in healthy Chinese subjects, respectively, compared with the corresponding PK parameters observed in a healthy Western population.15 Race was not identified as a statistically significant covariate affecting the PK of canagliflozin in the population PK analysis.20 Because lower weight was associated with higher exposures in the population PK analysis and the Chinese subjects had a lower weight than the Western counterparts, the higher exposures in Chinese subjects were likely due to their lower weight. The higher exposure in Chinese subjects was attenuated when exposures in the populations were normalized for weight, thus supporting differences in weight as an explanation for the difference in exposures. After normalizing to a 100-mg dose and a weight of 70 kg, median dose- and weight-normalized PK parameters in the Chinese population were similar to those obtained in a Western population (AUC, Chinese vs Western: 9492 vs 9579 ng h/mL) (Supplemental Table). There was also a strong overlap between the distributions and CIs of the different ethnic groups (Figure 3). The exposures in Chinese subjects were within the range seen in Western patients with T2DM treated with canagliflozin 300 mg BID for 12 weeks, and this dosing regimen was well tolerated.7,18 Median Tmax and mean apparent t½ values for canagliflozin and its metabolites were independent of dose. The mean M/P ratios obtained in this study for M7 and M5 were also consistent with findings of the ] 2015
Western population.15 Less than 1% of the dose was recovered in the urine as canagliflozin, whereas 17% of the dose was recovered as M7 and 9% dose was recovered as M5 metabolites. The dose recovered in urine as canagliflozin and its metabolites agreed with the findings from previous canagliflozin studies in nondiabetic subjects and in patients with T2DM in a Western population.13,14 Because the MDRD formula for estimating GFR has not been validated in Chinese subjects, RTG values were calculated by using 2 different estimates of GFR: MDRD and MCrCl. The values of RTG: MDRD were modestly higher than the RTG: MCrCl values because the MDRD-estimated GFR values are relatively higher than the MCrCl values. The reductions of 24-hour mean RTG: MCrCl with the 100- and 300-mg doses in these healthy subjects are similar to the effect size in a healthy Western population.14,15 With 100 mg and 300 mg of canagliflozin, the resultant 24-hour UGEs were modestly lower than those seen in Western populations.14,15 However, because the RTG: CrCL values were similar between Western and Chinese subjects, the lower UGE in Chinese subjects may be associated with their lower PG and MCrCl values (which affect the filtered glucose load and thereby influence the UGE) rather than being due to any major differences in sodium– glucose cotransporter 2 inhibition between a Chinese and a Western population.
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Dose/Weight-Normalized AUC (ng.h/mL)
Clinical Therapeutics
Placebo (n=14) Canagliflozin 100 mg (n=14) Canaliflozin 300 mg (n=14) 180
Plasma Glucose (mg/dL)
160
140
100
0
8
4
12 Time (h)
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15,000
10,000
5000 Total White (N=1616) (n=942)
120
80
20,000
140
120
100
Asian (n=245)
Chinese (n=14)
Figure 3. Box plots of the dose/weight-normalized canagliflozin AUC grouped according to ethnicity. Grey area ¼ 95% CI of the median; filled circles ¼ median; box ¼ interquartile range (contains 50% of data); horizontal dash ¼ outlier. “Asian” was identified as Asian in the case report form, and data from the population pharmacokinetic analysis for Total, White, and Asian participants were used to generate this graphic.16 Chinese participants (n ¼ 14): each participant received 2 doses (100 and 300 mg), and there were a total of 28 pharmacokinetic values included in this analysis; data were normalized to a 100-mg dose and a body weight of 70 kg.
80 0
1
2 Time (h)
3
4
Figure 2. Mean (SD) (A) plasma glucose concentration–time profiles and (B) postprandial plasma glucose concentration–time profiles after breakfast (first meal after dosing of canagliflozin or placebo).
The 24-hour PG profile was generally unchanged with the different canagliflozin doses, with the exception of a blunted postbreakfast peak glucose excursion observed with both doses of canagliflozin and a delayed rise in glucose after breakfast in subjects receiving canagliflozin 300 mg. The delay in the time
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to peak MPG with 300-mg canagliflozin, relative to 100-mg canagliflozin, was also apparent in the MPG0–2 with the 300-mg dose compared with the 100-mg dose. However, no changes in postprandial glucose excursions were observed after lunch or dinner in subjects receiving canagliflozin relative to those receiving placebo. The delayed rise in postprandial glucose concentrations observed with canagliflozin 300 mg is consistent with previous findings in a Western study, which showed that a single dose of 300-mg canagliflozin resulted in an additional, nonrenal reduction in postprandial glucose concentrations during the first meal after canagliflozin administration; this effect was likely due to the transient inhibition of intestinal sodium–glucose cotransporter 1 at high intestinal drug concentrations during drug absorption.30
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X. Chen et al. Canagliflozin was generally safe and well tolerated. All reported AEs were mild in severity. Overall, there were no safety findings of clinical concern. The safety profile in Chinese subjects was generally similar to that observed in a Phase III study performed in Chinese patients treated with canagliflozin.31,32
CONCLUSIONS The PK exposure parameters (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of the drug (100 and 300 mg) in healthy Chinese subjects. Tmax and t½ of canagliflozin were independent of the dose. Canagliflozin decreased 24-hour mean RTG and increased UGE in a dosedependent manner, and these findings are consistent with results observed in other patient populations. Canagliflozin was generally safe and well tolerated in these healthy Chinese subjects.
ACKNOWLEDGMENTS This study was funded by Janssen Research & Development, LLC. Dr. Shalini Nair (SIRO Clinpharm Pvt Ltd) provided writing assistance and Dr. Bradford Challis (Janssen Research & Development, LLC) provided additional editorial support for the development of the manuscript. The authors thank the study participants, without whom this study would not have been accomplished. Dr. Hu and Dr. Chen were investigators in the study and were involved in participant recruitment, study operation, study management, data collection, and review and finalization of the study protocol and report. Dr. Devineni, Dr. Polidori, Ms. Vaccaro, and Mr. Curtin contributed to the study design and data interpretation; Dr. Polidori and Ms. Vaccaro also contributed to data analysis; Dr. Devineni and Mr. Curtin wrote the protocol; Mr. Stieltjes was the bioanalytical scientist responsible for sample analyses; and Dr. Sha was the study physician and was also involved in data interpretation. All authors contributed to the data interpretation. All authors met International Committee of Medical Journal Editors criteria, and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, made the final decision about where to publish these data, and approved submission to the journal.
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CONFLICTS OF INTEREST Dr. Devineni, Dr. Sha, Dr. Polidori, Ms. Vaccaro, Mr. Curtin, and Mr. Weiner are employees of Janssen Research & Development, LLC, and Mr. Stieltjes is an employee of Janssen Research & Development, a division of Janssen Pharmaceutica NV; all hold stock in the company. Dr. Hu received research grant from Janssen R & D. The authors have indicated that they have no other conflicts of interest regarding the content of this article. The study sponsor was involved in the study design, analysis and interpretation of data, review of this manuscript; and in the decision to submit the manuscript for publication.
SUPPLEMENTARY MATERIAL Supplementary data associated with this article can be found in the online version at http://dx.doi.org/ 10.1016/j.clinthera.2015.04.015.
REFERENCES 1. World Health Organization. Diabetes Fact Sheet No. 312. http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed May 29, 2014. 2. Yang W. Changing characteristics of the type 2 diabetes epidemic of China and other Asian countries. J Diabetes Investig. 2013;4:223–224. 3. Cernea S, Raz I. Therapy in the early stage: incretins. Diabetes Care. 2011;34(Suppl 2):S264–S271. 4. Fowler MJ. Diabetes treatment, part 2: oral agents for glycemic management. Clin Diabetes. 2007;25:131–134. 5. Bode B, Stenlof K, Sullivan D, et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995). 2013;41:72–84. 6. Devineni D, Vaccaro N, Polidori D, et al. Effects of hydrochlorothiazide on the pharmacokinetics, pharmacodynamics, and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants. Clin Ther. 2014;36:698–710. 7. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35:1232–1238. 8. Neumiller JJ, White JR Jr, Campbell RK. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs. 2010;70:377–385. 9. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15:372–382.
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Clinical Therapeutics 10. Canagliflozin (Invokana™) Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2013. http://www.accessdata.fda.gov/drug s a t f d a _ d o c s / l a b e l / 2 013 / 204042s000lbl.pdf. Accessed on March 5, 2014. 11. European Medicines Agency. Assessment report: Canagliflozen. http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_ Public_assessment_report/human/ 002649/WC500156457.pdf. Accessed on March 29, 2015. 12. Canagliflozin (Invokana™) [prescribing information]. NSW. Australia: Janssen‐Cilag Pty Ltd; 2013. 13. Devineni D, Curtin CR, Polidori D, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2013;53:601–610. 14. Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13:669–672. 15. Devineni D, Vaccaro N, Polidori D, et al. Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants. Int J Clin Pharmacol Ther. 2015;53:129–138. 16. Devineni D, Manitpisitkul P, Murphy J, et al. Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, and assessment of dose proportionality in healthy participants. Clinical Pharm in Drug Dev. 2014. 17. European Medicines Agency. Invokana™. Summary of Product Characteristics. http://www.ema.europa. eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/ 002649/WC500156456.pdf. Accessed on August 19, 2014.
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18. Devineni D, Morrow L, Hompesch M, et al. Canagliflozin improves glycemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012;14:539–545. 19. Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther. 2008;84:417–423. 20. Hoeben E, Vermeulen A, De Winter W, et al. Population pharmacokinetic modeling of canagliflozin in healthy volunteers and patients with type 2 diabetes mellitus. Clin Pharmacokinet. 2013;52:1005–1015. 21. Sha S, Devineni D, Ghosh A, et al. Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes. PLoS One. 2014;9:e110069. 22. Inagaki N, Kondo K, Iwasaki T, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2 (SGLT2) improves glycemic control and reduces body weight in Japanese type 2 diabetes mellitus (T2DM). Poster presented at: 71st Scientific Session of the American Diabetes Association (ADA); June 24-28, 2011; San Diego, CA. Abstract # 0999-P. 23. Sakai M, Matsukawa M, Azuma J, et al. A study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a new SGLT2 inhibitor TA-7284/Canagliflozin in healthy Japanese subjects. Poster presented at: The 53rd Annual Meeting of the Japan Diabetes Society; May 27-29, 2010; Okayama, Japan. 24. Sinclair A, Bode B, Harris S, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14:37.
25. Usiskin K, Kline I, Fung A, et al. Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results. Postgrad Med. 2014;126:16–34. 26. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15:463–473. 27. Polidori D, Sha S, Ghosh A, et al. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2013;98:E867–E871. 28. Teo BW, Xu H, Wang D, et al. GFR estimating equations in a multiethnic Asian population. Am J Kidney Dis. 2011;58:56–63. 29. Ma YC, Zuo L, Chen JH, et al. Modified glomerular filtration rate estimation equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol. 2006;17:2937–2944. 30. Polidori D, Sha S, Mudaliar S, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care. 2013;36:2154–2161. 31. Ji L, Han P, Liu Y, et al. Canagliflozin in Asian subjects with type 2 diabetes on metformin (MET) alone or in combination with sulphonylurea (SU). Poster presented at: 22nd Biennial World Diabetes Congress of the International Diabetes Federation (IDF); December 2-6, 2013; Melbourne, Australia. 32. Ji L, Han P, Liu Y, et al. Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea. Diabetes Obes Metab. 2015;17:23–31.
Address correspondence to: Pei Hu, MD, Phase I Unit of Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China. E-mail: [email protected]
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X. Chen et al.
SUPPLEMENTARY MATERIAL Supplemental Table. Descriptive statistics of the dose/weight-normalized canagliflozin AUC grouped according to ethnicity. Ethnicity Population PK analysis Total (N ¼ 1616) Western (n ¼ 942) Asian (n ¼ 245) Phase I study: Chinese (N ¼ 14*)
Median (ng h/mL)
5% Quantile (ng h/mL)
95% Quantile (ng h/mL)
9232 9579 7883 9492
6017 6292 5463 7812
15,035 15,804 12,403 12,532
PK ¼ pharmacokinetics. * Each participant in the Chinese study received 2 doses (100 and 300 mg), and a total of 28 PK values were included in the analysis; data were normalized to a 100-mg dose and a weight of 70 kg.
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Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects Xia Chen, MD1; Pei Hu, MD1; Nicole Vaccaro, BS2; David Polidori, PhD2; Christopher R. Curtin, BS3; Hans Stieltjes, MSc4; Sue Sha, MD, PhD3; Sveta Weiner, MS3; and Damayanthi Devineni, PhD3 1
Phase I Unit of Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China; 2Janssen Research & Development, LLC, San Diego, California; 3Janssen Research & Development, LLC, Raritan, New Jersey; and 4Janssen Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium
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 (AUC0–1, 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 AUC0–1 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 24hour increased urinary glucose excretion (33.8 and
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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. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: canagliflozin, pharmacodynamics, pharmacokinetics, safety, sodium-glucose cotransporter 2 inhibitor.
INTRODUCTION Type 2 diabetes mellitus (T2DM) is a growing concern, accounting for 490% of the diagnosed cases of diabetes worldwide.1 In China, the diabetes epidemic is accelerating at an alarming rate, with 92.4 million adults estimated to be diabetic.2 Although many Accepted for publication April 30, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.04.015 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics medications are available for the management of this disease, the use of antihyperglycemic agents is often limited by weight gain, episodes of hypoglycemia, edema, potential cardiovascular disorders, and/or adverse gastrointestinal effects.3,4 Canagliflozin,* a sodium–glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.5–7 It acts on the proximal renal tubules, thereby reducing glucose reabsorption and increasing urinary glucose excretion (UGE). This novel insulin-independent approach lowers plasma glucose (PG) and increases caloric loss (4 kcal/g of glucose).8,9 The recommended starting dose of canagliflozin is 100 mg/d, to be administered before the first meal of the day; in patients with an estimated glomerular filtration rate (eGFR) of Z60 mL/min/1.73 m2 who require additional glycemic control, the dosage may be increased to 300 mg/d.9–12 Canagliflozin is mostly metabolized through the O‐glucuronidation metabolic elimination pathway, and the 2 major metabolites are the inactive M5 and M7 O‐glucuronide conjugates of the unchanged drug.13,14 The pharmacokinetic (PK) characteristics of canagliflozin have been evaluated after single and multiple oral dose administration in healthy subjects and in patients with T2DM in Western populations.13–15 After oral administration in healthy subjects and in patients with T2DM, canagliflozin was rapidly absorbed, with the median Tmax occurring 1 to 2 hours postdose.16 In healthy subjects, the mean AUC of canagliflozin increased in a dose-dependent manner across a wide range of doses (25–1600 mg), whereas Cmax increased in a dose-proportional manner from 50 to 300 mg16,17 and even up to 1200 mg (unpublished data). In patients with T2DM, the Cmax and AUC of canagliflozin also increased in a linear manner over the dose range of 50 to 300 mg.13 Mean terminal t½ ranged from 10.6 to 13.1 hours with the 100- and 300-mg doses. No dose-related clinical adverse drug reactions were reported for single doses up to 1600 mg of canagliflozin in healthy subjects (unpublished data). The highest multiple-dose canagliflozin regimen evaluated in clinical studies was 300 mg BID, which was used both in a 4-week dose-ranging study in patients Trademark: Invokanas (Janssen Pharmaceuticals, Inc, Titusville, New Jersey).
*
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with T2DM18 and in a 12-week, Phase II dose-ranging study in patients with T2DM.7 It was found to be safe and generally well tolerated in both studies. Ethnicity is one factor that may account for the observed differences in both PK and pharmacodynamics (PD) of drugs, resulting in variability in response to drug therapy.19 The dose- and weightnormalized PK parameters of canagliflozin demonstrated no apparent differences in canagliflozin exposure among healthy Western, Indian, and Japanese subjects, as well as between Western and Japanese patients with T2DM.20 Moreover, after canagliflozin treatment at comparable doses, the PD parameters (UGE, both 24-hour and fasting PG, and renal threshold for glucose excretion [RTG]) exhibited a similar pattern of dose-dependent changes in Western,13–15 Korean,21 and Japanese patients with T2DM.22,23 To further explore potential interethnic differences in the PK and PD characteristics of canagliflozin, a Phase I study was conducted in healthy Chinese subjects. The doses selected for the present study (100 and 300 mg) were previously evaluated in healthy Western subjects and were found to be generally well tolerated.14,15 In addition, these doses were shown to be efficacious in global Phase III trials in patients with T2DM.9,24–26
SUBJECTS AND METHODS Study Population Fifteen healthy Chinese men and women, aged between 18 and 55 years, with a body mass index between 18 and 28 kg/m2 and weight Z50 kg, were enrolled. Participants were excluded from the study if there was evidence of the following: any clinically significant medical illness, history of smoking or drug or alcohol abuse, or known allergy to canagliflozin. Pregnant or breastfeeding women were also excluded. Subjects were prohibited from taking any over-thecounter or prescribed medications except acetaminophen for at least 14 days before study initiation and throughout the study. Women on hormone replacement therapy or contraceptives continued the same medication throughout the study. The study protocol was approved by the local independent ethics committee and was conducted in accordance with the ethical principles originating in the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice Guideline, and applicable regulatory requirements and in
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X. Chen et al. compliance with the protocol. All participants provided written informed consent to participate in the study.
sample were stored at 201C or lower until transferred to a bioanalytical facility.
PK and PD Analytical Methods Study Design and Treatment This single-center, double-blind, randomized, placebo-controlled, single-dose, 3-way crossover study consisted of 3 phases: the screening phase (3 weeks), a treatment phase (including three 5-day treatment periods and 2 interperiod washout sessions of at least 10 days), and the safety follow-up phase (7–10 days) after completion of the third treatment period. Eligible participants were randomized to 1 of 3 treatment sequence groups (ABC, BCA, or CAB) by using a computer-generated randomization schedule. Subjects received canagliflozin 100 mg (treatment A), canagliflozin 300 mg (treatment B), and placebo (treatment C) based on their randomized treatment sequence group. The study drugs were administered 10 minutes before a standardized breakfast on all dosing days.
Clinical Evaluations PK Sample Collection Blood samples (3 mL) for the bioassays of canagliflozin and its metabolites M7 and M5 were collected into dipotassium EDTA tubes at predose and at 0.5, 1, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose during each treatment period. The samples were cool-centrifuged (10 minutes at 1300 g), and the obtained plasma was stored at 201C or lower. Urine samples for the measurement of canagliflozin and M7 and M5 concentrations were collected in the following time intervals: 0 to 4, 4 to 10, 10 to 13, 13 to 24, and 24 to 48 hours postdose during each treatment period. The total volume of the urine over each time interval was recorded, and an aliquot of each urine sample was stored at 201C or lower until further analyses were conducted.
PD Sample Collection PG was assessed by using blood samples (2 mL) obtained at predose as well as 10 minutes and 0.5, 1, 1.5, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 11, 11.5, 12, 13, 14, 16, and 24 hours postdose during each treatment period. Urine samples (10 mL) were collected over the predefined intervals of 0 to 4, 4 to 10, 10 to 13, 13 to 24, and 24 to 48 hours postdose for determination of UGE. All plasma samples and an aliquot of each urine
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The concentrations of canagliflozin and its metabolites in plasma and urine samples were determined by using previously described,13 validated (plasma) or qualified (urine) specific, sensitive LC-MS/MS methods at Frontage Laboratories (Shanghai) Co, Ltd (Shanghai, China). In brief, the methods consisted of a liquid– liquid extraction with tertiary butyl methyl ether, followed by LC-MS/MS analysis using isocratic reversed-phase chromatography on a C18 column. The bioanalytical methods for canagliflozin and its metabolites M7 and M5 in plasma had a calibration range of 5 to 10,000 ng/mL. The calibration range in urine was 25 to 10,000 ng/mL for canagliflozin and 100 to 100,000 ng/mL for M7 and M5. All bioanalytical runs met the predefined acceptance criteria. Plasma and urine samples were analyzed to determine concentrations of glucose by using conventional laboratory testing at Covance Central Laboratory Services SA (Geneva, Switzerland).
PK and PD Analyses The plasma PK parameters were determined for canagliflozin, M7, and M5 based on individual plasma concentration–time profiles, using actual sampling times, according to noncompartmental analysis with validated WinNonlin version 5.3 software (Pharsight Corporation, Mountainview, California). Key PK parameters included: Cmax, Tmax, t½, AUC0–1 (calculated as the sum of AUC0–last and C0–last/λz [terminal slope]), CL/F (for the parent compound only), the metabolite to parent ratio for Cmax (M/P Cmax ratio, metabolites only), and the metabolite to parent ratio for AUC0–1 (M/P AUC0–1 ratio, metabolites only). The following urine PK parameters for canagliflozin, M7, and M5 were determined: cumulative amount excreted in the urine, expressed as a percentage of the administered dose, corrected for molecular weight only for metabolites, and renal clearance (CLR). Key PD parameters included RTG, calculated for each scheduled urine collection interval and for each 24-hour urine collection period; UGE, defined as the amount of glucose excreted into the urine over the entire urine collection interval (0–24 hours) and
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Clinical Therapeutics calculated as the sum of all the UGEt1–t2 values from 0 to 24 hours postdose; and mean plasma glucose (MPG), calculated as the MPG concentration from time 0 to 24 hours after dosing. The values of MPG0–24 were determined from the measured PG profiles by calculating the AUC (using the linear trapezoidal rule) from 0 to 24 hours and dividing by 24 hours (calculations performed by using WinNonlin version 5.2.1; Pharsight Corporation). Postprandial mean incremental PG concentrations during the 0 to 2 hour (MΔPG0–2) and the 0 to 4 hour (MΔPG0–4) intervals were calculated as the positive incremental areas under the PG profile and above the premeal PG concentration. Values of RTG were calculated during each collection interval by using the measured PG profiles, UGE, and eGFR as described previously.14,27 Because the commonly used Modification of Diet in Renal Disease (MDRD) formula for eGFR has not yet been validated in Chinese subjects, the RTG values were calculated by using 2 separate estimates for GFR: eGFR from the MDRD formula (denoted as RTG: MDRD) and measured 24-hour creatinine clearance (MCrCl) (denoted as RTG: MCrCl).28,29 The 24-hour mean RTG values were calculated as the weighted mean of the RTG values obtained over individual urine collection intervals (the RTG value over each interval was multiplied by the duration of the interval, and the sum of these values was divided by 24 hours).
Safety Assessments Safety evaluations included assessments of treatmentemergent adverse events (TEAEs), changes in routine clinical laboratory test results, vital sign measurements (blood pressure, pulse rate, and body temperature), physical examinations, 12-lead ECGs, and documentation of hypoglycemic episodes at predefined time points.
Statistical Analysis Sample Size Based on data from earlier Phase I studies of canagliflozin in healthy subjects, the intersubject % CV for Cmax and AUC of canagliflozin after singledose administration was estimated to be r30%. Based on an estimated intersubject %CV of r30% for Cmax and AUC of canagliflozin after single-dose administration, a sample size of 12 subjects was considered sufficient for the point estimate of
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geometric means of Cmax and AUC0–1 to fall within 83% and 121% of the true value with 95% confidence. Based on an estimated intersubject %CV of 35% for 24-hour mean RTG, a sample size of 12 completed subjects was considered sufficient for the point estimate of the geometric 24-hour mean RTG for each canagliflozin dose to fall within 80% and 125% of the true value with 95% confidence. Based on an intersubject SD of 8 g for UGE0–24, a sample size of 12 completed subjects was considered sufficient for the point estimate of the arithmetic mean UGE0–24 for each canagliflozin dose to be within ⫾5.1 g of the true value with 95% confidence. Fifteen participants were enrolled to allow for potential dropouts.
PK, PD, and Safety Profile All participants who completed the study were included in the PK and PD analyses. All participants who were randomly assigned to treatment and received at least 1 dose of the study drug were included in the safety and tolerability analyses. The PK, PD, and safety findings were summarized descriptively.
RESULTS Patient Disposition and Demographic Characteristics This study was conducted at a single center in Beijing, China, from July 2012 to August 2012. Fifteen healthy Chinese subjects (9 men, 6 women) were enrolled; all subjects received the study drug, and 14 (93%) completed the study. One female subject receiving 100 mg of canagliflozin withdrew consent prematurely for personal reasons after dosing on day 1 of period 1. Baseline characteristics of subjects are summarized in Table I.
Pharmacokinetics After single-dose administration of canagliflozin, plasma canagliflozin concentrations increased rapidly at both dose levels (100 and 300 mg), with median Tmax values of 1 hour (Figure 1). Mean Cmax and AUC0–1 values for canagliflozin increased in a dosedependent manner. Mean apparent t½ values were 16.0 hours and appeared to be independent of dose in this study. Mean CL/F and CLR were similar between the 2 doses (CL/F [L/h], 9.78 [1.84] and 9.26 [1.99] for 100 mg and 300 mg, respectively; CLR [L/h], 0.0514 [0.0187] and 0.0472 [0.00704] for 100 mg and 300 mg). Less
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X. Chen et al. than 1% of the administered dose was excreted in the urine as canagliflozin over the 48-hour urine collection period after a single dose (Table II). The plasma concentrations of M7 and M5 also increased rapidly after single-dose administration of 100- and 300-mg canagliflozin. Median Tmax values were 2 hours (range, 1.5–6 hours for 100 mg; 1.5–3 hours for 300 mg) and 3.5 hours (range, 2–4 hours for 100 mg; 1.5–4 hours for 300 mg) for M7 and M5, respectively (Figure 1). Mean terminal t½ values were 15 hours for both M7 and M5. With the investigated doses studied, 17% of the administered dose was recovered as M7 and 9% was recovered as M5 in the urine over the 48-hour period after single-dose canagliflozin administration. The mean M7 and M5 metabolite to parent (M/P) molar ratios (corrected for differences in molecular weights) for Cmax and AUC0–1 were similar between the 2 doses (Table II).
Table I. Demographic and baseline characteristics (safety analysis set). Study Population (N ¼ 15)
Characteristic Age, y* Sex, no. (%) Female Male Weight, kg* Body mass index, kg/m2*,† eGFR, mL/min/1.73 m2*
29.5 (4.90) 6 9 63.0 22.0 103
(40) (60) (7.32) (2.08) (11.44)
eGFR ¼ estimated glomerular filtration rate. * Mean (SD). † Obtained by using the Modification of Diet in Renal Disease formula.
Plasma Canagliflozin (ng/mL)
10,000 Canagliflozin 100 mg (n=14) Canaliflozin 300 mg (n=14) 1000
100
10 12
24
48 36 Time (h)
60
72
10,000
10,000
1000
1000
M5 (ng/mL)
M7 (ng/mL)
0
100
100
10
10 0
12
24
48 36 Time (h)
60
72
0
12
24
48 36 Time (h)
60
72
Figure 1. Plasma concentration–time profiles of (A) canagliflozin, (B) M7, and (C) M5 after administration of canagliflozin in healthy Chinese subjects.
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5
6
517 (148) 3.50 (2.00–4.00) 8006 (2502) 14.2 (3.21) 8.78 (2.94) — — 0.328 (0.08) 0.564 (0.17) 2155 (671) 2.00 (1.50–3.00) 26,302 (6381) 15.5 (4.25) 17.0 (3.39) — — 0.387 (0.11) 0.598 (0.20) 745 (265) 2.00 (1.50–6.00) 9050 (2502) 15.1 (3.62) 17.5 (5.23) — — 0.474 (0.15) 0.651 (0.22) 1178 (291) 1.00 (1.00–3.00) 10,521 (1707) 16.0 (4.13) 0.496 (0.21) 9.78 (1.84) 0.0514 (0.02) — — Cmax, ng/mL Tmax, h* AUC0–1, ng h/mL t½, h Ae % dose CL/F, L/h CLR, L/h M/P Cmax ratio M/P AUC0–1 ratio
4113 (665) 1.25 (1.00–1.50) 33,583 (6100) 16.2 (4.79) 0.481 (0.12) 9.26 (1.99) 0.0472 (0.01) — —
100 mg (n ¼ 14) 300 mg (n ¼ 14) 100 mg (n ¼ 14) Parameter
Ae % dose ¼ total amount excreted into the urine during a 24-hour dosing interval (expressed as a percentage of the administered dose); CLR ¼ renal clearance; M/P AUC1 ratio ¼ metabolite to parent (M/P) ratio for AUC1 corrected for molecular weight; M/P Cmax ratio ¼ metabolite-to-parent (M/P) ratio for Cmax. * Median (range).
1553 (474) 3.00 (1.50–4.00) 25,269 (8859) 15.2 (4.38) 8.83 (2.47) — — 0.276 (0.07) 0.561 (0.19)
300 mg (n ¼14) 100 mg (n ¼ 14) 300 mg (n ¼ 14)
M5 M7 Canagliflozin
Table II. Mean (SD) pharmacokinetic parameters of canagliflozin and its metabolites after administration of canagliflozin in healthy Chinese subjects.
Clinical Therapeutics
Pharmacodynamics Canagliflozin altered UGE and 24-hour mean RTG in a dose-dependent manner. The mean UGE0–24 was 33.8 and 42.9 g with the canagliflozin 100- and 300-mg doses, respectively (Table III). RTG values could not be calculated for the subjects receiving placebo because they had virtually no UGE; commonly quoted values of RTG in healthy subjects are 180 to 200 mg/dL.14 Using eGFR according to the MDRD formula, canagliflozin 100 mg and 300 mg decreased the mean RTG: MDRD to 76 and 68 mg/dL, respectively. When using MCrCl for eGFR, mean RTG: MCrCl values of 68 and 61 mg/dL were obtained with 100 mg and 300 mg of canagliflozin. The 24-hour PG profile was generally unchanged by canagliflozin (Figure 2A), with the exception of a blunted peak glucose excursion observed postbreakfast with both doses of canagliflozin and a delayed rise in postbreakfast PG in subjects receiving canagliflozin 300 mg (Table III, Figure 2B).
Safety Profile Treatment with both doses of canagliflozin (100 and 300 mg) was generally well tolerated. No deaths, serious adverse events, discontinuation due to TEAEs, hypoglycemic events, or persistent TEAEs were reported during the study. The incidence of TEAEs was 33.3% (5 of 15) with canagliflozin 100 mg, 33.3% (5 of 15) with placebo, and 13.3% (2 of 15) with canagliflozin 300 mg. The most commonly reported (45% participants) TEAEs were increased levels of blood bilirubin (canagliflozin 100 mg, 1 [6.7%]; placebo, 1 [7.1%]), presence of white blood cells in urine (canagliflozin 100 mg, 1 [6.7%]; canagliflozin 300 mg, 1 [7.1%]), dizziness (canagliflozin 100 mg, 1 [6.7%]; placebo, 1 [7.1%]), and vulvovaginal pruritus (canagliflozin 100 mg, 2 [13.3%]). All reported AEs were mild in severity as assessed by the investigator. There were no clinically relevant changes in other laboratory findings, vital signs, physical examinations, or ECG parameters.
DISCUSSION This Phase I study evaluated the PK, PD, and safety profile of canagliflozin in healthy Chinese subjects. After oral administration, canagliflozin was rapidly absorbed, and the exposure of canagliflozin and its metabolites increased in a dose-dependent manner. The mean plasma Cmax and AUC0–1 were 14% Volume ] Number ]
X. Chen et al.
Table III. Mean (SD) pharmacodynamic parameters of canagliflozin after administration of canagliflozin in healthy Chinese subjects. Placebo (n ¼ 14)
Parameter 24-hour mean RTG: 24-hour mean RTG: UGE0–24, g MPG0–24, mg/dL MΔPG0–2, mg/dL MΔPG0–4, mg/dL
MDRD, MCrCl,
mg/dL mg/dL
— — 0.009 (0.01) 99.4 (6.56) 30.5 (17.60) 20.5 (12.50)
Canagliflozin 100 mg (n ¼ 14) 76.2 67.9 33.8 98.2 23.0 16.0
(8.65) (14.10) (10.40) (6.34) (10.60) (7.03)
Canagliflozin 300 mg (n ¼ 14) 67.4 60.7 42.9 96.9 15.5 14.2
(5.14) (9.58) (6.67) (4.64) (10.00) (9.37)
RTG ¼ renal threshold for glucose excretion; RTG: MDRD ¼ RTG calculated by using the Modification of Diet in Renal Disease formula; RTG: MCrCl ¼ RTG calculated by using measured 24-hour creatinine clearance; UGE ¼ urinary glucose excretion; MPG0–24 ¼ mean plasma glucose concentration defined as the AUC0–24 postdose divided by 24; MΔPG0–2 ¼ mean incremental plasma glucose concentration from 0 to 2 hours; MΔPG0–4 ¼ mean incremental plasma glucose concentration from 0 to 4 hours.
to 42% and 57% to 62% higher in healthy Chinese subjects, respectively, compared with the corresponding PK parameters observed in a healthy Western population.15 Race was not identified as a statistically significant covariate affecting the PK of canagliflozin in the population PK analysis.20 Because lower weight was associated with higher exposures in the population PK analysis and the Chinese subjects had a lower weight than the Western counterparts, the higher exposures in Chinese subjects were likely due to their lower weight. The higher exposure in Chinese subjects was attenuated when exposures in the populations were normalized for weight, thus supporting differences in weight as an explanation for the difference in exposures. After normalizing to a 100-mg dose and a weight of 70 kg, median dose- and weight-normalized PK parameters in the Chinese population were similar to those obtained in a Western population (AUC, Chinese vs Western: 9492 vs 9579 ng h/mL) (Supplemental Table). There was also a strong overlap between the distributions and CIs of the different ethnic groups (Figure 3). The exposures in Chinese subjects were within the range seen in Western patients with T2DM treated with canagliflozin 300 mg BID for 12 weeks, and this dosing regimen was well tolerated.7,18 Median Tmax and mean apparent t½ values for canagliflozin and its metabolites were independent of dose. The mean M/P ratios obtained in this study for M7 and M5 were also consistent with findings of the ] 2015
Western population.15 Less than 1% of the dose was recovered in the urine as canagliflozin, whereas 17% of the dose was recovered as M7 and 9% dose was recovered as M5 metabolites. The dose recovered in urine as canagliflozin and its metabolites agreed with the findings from previous canagliflozin studies in nondiabetic subjects and in patients with T2DM in a Western population.13,14 Because the MDRD formula for estimating GFR has not been validated in Chinese subjects, RTG values were calculated by using 2 different estimates of GFR: MDRD and MCrCl. The values of RTG: MDRD were modestly higher than the RTG: MCrCl values because the MDRD-estimated GFR values are relatively higher than the MCrCl values. The reductions of 24-hour mean RTG: MCrCl with the 100- and 300-mg doses in these healthy subjects are similar to the effect size in a healthy Western population.14,15 With 100 mg and 300 mg of canagliflozin, the resultant 24-hour UGEs were modestly lower than those seen in Western populations.14,15 However, because the RTG: CrCL values were similar between Western and Chinese subjects, the lower UGE in Chinese subjects may be associated with their lower PG and MCrCl values (which affect the filtered glucose load and thereby influence the UGE) rather than being due to any major differences in sodium– glucose cotransporter 2 inhibition between a Chinese and a Western population.
7
Dose/Weight-Normalized AUC (ng.h/mL)
Clinical Therapeutics
Placebo (n=14) Canagliflozin 100 mg (n=14) Canaliflozin 300 mg (n=14) 180
Plasma Glucose (mg/dL)
160
140
100
0
8
4
12 Time (h)
20
16
24
160
Plasma Glucose (mg/dL)
15,000
10,000
5000 Total White (N=1616) (n=942)
120
80
20,000
140
120
100
Asian (n=245)
Chinese (n=14)
Figure 3. Box plots of the dose/weight-normalized canagliflozin AUC grouped according to ethnicity. Grey area ¼ 95% CI of the median; filled circles ¼ median; box ¼ interquartile range (contains 50% of data); horizontal dash ¼ outlier. “Asian” was identified as Asian in the case report form, and data from the population pharmacokinetic analysis for Total, White, and Asian participants were used to generate this graphic.16 Chinese participants (n ¼ 14): each participant received 2 doses (100 and 300 mg), and there were a total of 28 pharmacokinetic values included in this analysis; data were normalized to a 100-mg dose and a body weight of 70 kg.
80 0
1
2 Time (h)
3
4
Figure 2. Mean (SD) (A) plasma glucose concentration–time profiles and (B) postprandial plasma glucose concentration–time profiles after breakfast (first meal after dosing of canagliflozin or placebo).
The 24-hour PG profile was generally unchanged with the different canagliflozin doses, with the exception of a blunted postbreakfast peak glucose excursion observed with both doses of canagliflozin and a delayed rise in glucose after breakfast in subjects receiving canagliflozin 300 mg. The delay in the time
8
to peak MPG with 300-mg canagliflozin, relative to 100-mg canagliflozin, was also apparent in the MPG0–2 with the 300-mg dose compared with the 100-mg dose. However, no changes in postprandial glucose excursions were observed after lunch or dinner in subjects receiving canagliflozin relative to those receiving placebo. The delayed rise in postprandial glucose concentrations observed with canagliflozin 300 mg is consistent with previous findings in a Western study, which showed that a single dose of 300-mg canagliflozin resulted in an additional, nonrenal reduction in postprandial glucose concentrations during the first meal after canagliflozin administration; this effect was likely due to the transient inhibition of intestinal sodium–glucose cotransporter 1 at high intestinal drug concentrations during drug absorption.30
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X. Chen et al. Canagliflozin was generally safe and well tolerated. All reported AEs were mild in severity. Overall, there were no safety findings of clinical concern. The safety profile in Chinese subjects was generally similar to that observed in a Phase III study performed in Chinese patients treated with canagliflozin.31,32
CONCLUSIONS The PK exposure parameters (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of the drug (100 and 300 mg) in healthy Chinese subjects. Tmax and t½ of canagliflozin were independent of the dose. Canagliflozin decreased 24-hour mean RTG and increased UGE in a dosedependent manner, and these findings are consistent with results observed in other patient populations. Canagliflozin was generally safe and well tolerated in these healthy Chinese subjects.
ACKNOWLEDGMENTS This study was funded by Janssen Research & Development, LLC. Dr. Shalini Nair (SIRO Clinpharm Pvt Ltd) provided writing assistance and Dr. Bradford Challis (Janssen Research & Development, LLC) provided additional editorial support for the development of the manuscript. The authors thank the study participants, without whom this study would not have been accomplished. Dr. Hu and Dr. Chen were investigators in the study and were involved in participant recruitment, study operation, study management, data collection, and review and finalization of the study protocol and report. Dr. Devineni, Dr. Polidori, Ms. Vaccaro, and Mr. Curtin contributed to the study design and data interpretation; Dr. Polidori and Ms. Vaccaro also contributed to data analysis; Dr. Devineni and Mr. Curtin wrote the protocol; Mr. Stieltjes was the bioanalytical scientist responsible for sample analyses; and Dr. Sha was the study physician and was also involved in data interpretation. All authors contributed to the data interpretation. All authors met International Committee of Medical Journal Editors criteria, and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, made the final decision about where to publish these data, and approved submission to the journal.
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CONFLICTS OF INTEREST Dr. Devineni, Dr. Sha, Dr. Polidori, Ms. Vaccaro, Mr. Curtin, and Mr. Weiner are employees of Janssen Research & Development, LLC, and Mr. Stieltjes is an employee of Janssen Research & Development, a division of Janssen Pharmaceutica NV; all hold stock in the company. Dr. Hu received research grant from Janssen R & D. The authors have indicated that they have no other conflicts of interest regarding the content of this article. The study sponsor was involved in the study design, analysis and interpretation of data, review of this manuscript; and in the decision to submit the manuscript for publication.
SUPPLEMENTARY MATERIAL Supplementary data associated with this article can be found in the online version at http://dx.doi.org/ 10.1016/j.clinthera.2015.04.015.
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Clinical Therapeutics 10. Canagliflozin (Invokana™) Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2013. http://www.accessdata.fda.gov/drug s a t f d a _ d o c s / l a b e l / 2 013 / 204042s000lbl.pdf. Accessed on March 5, 2014. 11. European Medicines Agency. Assessment report: Canagliflozen. http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_ Public_assessment_report/human/ 002649/WC500156457.pdf. Accessed on March 29, 2015. 12. Canagliflozin (Invokana™) [prescribing information]. NSW. Australia: Janssen‐Cilag Pty Ltd; 2013. 13. Devineni D, Curtin CR, Polidori D, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2013;53:601–610. 14. Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13:669–672. 15. Devineni D, Vaccaro N, Polidori D, et al. Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants. Int J Clin Pharmacol Ther. 2015;53:129–138. 16. Devineni D, Manitpisitkul P, Murphy J, et al. Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, and assessment of dose proportionality in healthy participants. Clinical Pharm in Drug Dev. 2014. 17. European Medicines Agency. Invokana™. Summary of Product Characteristics. http://www.ema.europa. eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/ 002649/WC500156456.pdf. Accessed on August 19, 2014.
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18. Devineni D, Morrow L, Hompesch M, et al. Canagliflozin improves glycemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012;14:539–545. 19. Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther. 2008;84:417–423. 20. Hoeben E, Vermeulen A, De Winter W, et al. Population pharmacokinetic modeling of canagliflozin in healthy volunteers and patients with type 2 diabetes mellitus. Clin Pharmacokinet. 2013;52:1005–1015. 21. Sha S, Devineni D, Ghosh A, et al. Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes. PLoS One. 2014;9:e110069. 22. Inagaki N, Kondo K, Iwasaki T, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2 (SGLT2) improves glycemic control and reduces body weight in Japanese type 2 diabetes mellitus (T2DM). Poster presented at: 71st Scientific Session of the American Diabetes Association (ADA); June 24-28, 2011; San Diego, CA. Abstract # 0999-P. 23. Sakai M, Matsukawa M, Azuma J, et al. A study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a new SGLT2 inhibitor TA-7284/Canagliflozin in healthy Japanese subjects. Poster presented at: The 53rd Annual Meeting of the Japan Diabetes Society; May 27-29, 2010; Okayama, Japan. 24. Sinclair A, Bode B, Harris S, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14:37.
25. Usiskin K, Kline I, Fung A, et al. Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results. Postgrad Med. 2014;126:16–34. 26. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15:463–473. 27. Polidori D, Sha S, Ghosh A, et al. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2013;98:E867–E871. 28. Teo BW, Xu H, Wang D, et al. GFR estimating equations in a multiethnic Asian population. Am J Kidney Dis. 2011;58:56–63. 29. Ma YC, Zuo L, Chen JH, et al. Modified glomerular filtration rate estimation equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol. 2006;17:2937–2944. 30. Polidori D, Sha S, Mudaliar S, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care. 2013;36:2154–2161. 31. Ji L, Han P, Liu Y, et al. Canagliflozin in Asian subjects with type 2 diabetes on metformin (MET) alone or in combination with sulphonylurea (SU). Poster presented at: 22nd Biennial World Diabetes Congress of the International Diabetes Federation (IDF); December 2-6, 2013; Melbourne, Australia. 32. Ji L, Han P, Liu Y, et al. Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea. Diabetes Obes Metab. 2015;17:23–31.
Address correspondence to: Pei Hu, MD, Phase I Unit of Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China. E-mail: [email protected]
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SUPPLEMENTARY MATERIAL Supplemental Table. Descriptive statistics of the dose/weight-normalized canagliflozin AUC grouped according to ethnicity. Ethnicity Population PK analysis Total (N ¼ 1616) Western (n ¼ 942) Asian (n ¼ 245) Phase I study: Chinese (N ¼ 14*)
Median (ng h/mL)
5% Quantile (ng h/mL)
95% Quantile (ng h/mL)
9232 9579 7883 9492
6017 6292 5463 7812
15,035 15,804 12,403 12,532
PK ¼ pharmacokinetics. * Each participant in the Chinese study received 2 doses (100 and 300 mg), and a total of 28 PK values were included in the analysis; data were normalized to a 100-mg dose and a weight of 70 kg.
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