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Original Research
1.
Introduction
2.
Patients and methods
3.
Results
4.
Discussion
5.
Conclusions
Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin in Japanese healthy male volunteers Shuji Kinoshita† & Kazuoki Kondo †
Department of Clinical Pharmacology, Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
Objectives: To investigate the pharmacokinetic/pharmacodynamic interactions of the antidiabetic agents canagliflozin (a sodium-glucose cotransporter-2 inhibitor) and teneligliptin (a dipeptidyl peptidase-4 inhibitor) in Japanese healthy adult men. Methods: Open-label, one-way crossover study used canagliflozin (200 mg/day p.o.) and teneligliptin (40mg/day p.o). A single dose of object drug (either canagliflozin or teneligliptin) was administered on day 1 followed by washout and continuous administration of precipitant drug (days 1 -- 9). Both drugs were concomitantly administered on day 7. Results: No changes in AUC0 -- 72h and Cmax were observed for canagliflozin +teneligliptin versus monotherapy; geometric mean ratios for AUC0 -- 72h and Cmax were 0.982 and 0.982 for the plasma concentration of canagliflozin and 0.983 and 0.976 for the plasma concentration of teneligliptin, respectively. Plasma concentrations of active and total glucagon-like peptide-1 (GLP-1) increased with canagliflozin+teneligliptin versus teneligliptin alone. Mean AUC0.5 -- 4h increased post-meal, on combination therapy, from 9.6 to 12.5 pmolh/l (active GLP-1) and from 21.5 to 32.3 pmolh/l (total GLP-1). Adverse events developed in four subjects; all were mild and resolved but one subject withdrew due to generalized erythema. Conclusions: GLP-1 levels increased with the canagliflozin+teneligliptin combination, and no PK interaction was observed. This combination may show favorable antidiabetic effects without increasing systemic exposure. Keywords: canagliflozin, DPP-4 inhibitor, drug-drug interaction, SGLT2 inhibitor, teneligliptin Expert Opin. Drug Metab. Toxicol. (2015) 11(1):7-14
1.
Introduction
Canagliflozin, a selective sodium-glucose cotransporter (SGLT)-2 inhibitor, is a novel antidiabetic drug that lowers blood glucose levels via a new mechanism of action, whereby it inhibits glucose reabsorption in the renal tubule, thus promoting glucose excretion into the urine [1,2]. Teneligliptin, on the other hand, increases circulating plasma levels of biologically active glucagon-like peptide-1 (GLP-1) by inhibiting the DPP-4 enzyme and, thereby, lowers blood glucose by promoting insulin secretion and suppressing glucagon secretion in a blood-glucose-dependent manner [3,4]. Both canagliflozin and teneligliptin are considered effective as treatments for type 2 diabetes mellitus, despite differences in their therapeutic targets and mechanisms of action. Therefore, coadministration of canagliflozin and 10.1517/17425255.2015.982531 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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S. Kinoshita & K. Kondo
teneligliptin is expected to achieve a satisfactory therapeutic effect in patients who have responded poorly to either agent alone. We expect that combination therapy with these two agents would enhance the effects of conventional therapy, with the possibility of pharmacodynamic interactions that could potentiate therapeutic effects following the addition of a new drug. However, pharmacokinetic interactions pose a concern for the use of combination therapy. Following oral administration and absorption in humans, canagliflozin is mainly eliminated by the uridine diphosphate glucuronosyltransferase (UGT) 1A9 and UGT2B4 metabolic enzymes. CYP3A4 is partly involved in the metabolism of canagliflozin [5]. In addition, canagliflozin is a substrate of the transporters p-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) [5]. For teneligliptin, after oral administration and absorption in humans, approximately 66 -- 80% of the drug is eliminated by metabolism and approximately 20 -- 34% undergoes urinary excretion via the kidneys [6]. CYP3A4 and flavin-containing monooxygenase (FMO3) are the main enzymes involved in the metabolism of teneligliptin [6], which also behaves as a substrate for P-gp [7]. Although these pharmacokinetic properties of canagliflozin and teneligliptin have been determined, the possibility and extent of pharmacokinetic interactions between canagliflozin and teneligliptin, when administered concomitantly, have not been investigated. With regard to pharmacodynamic interactions, a high dose of canagliflozin (300 mg) was reported to increase plasma GLP-1 levels when administered in the absence of a DPP-4 inhibitor to healthy adults [8]. However, the pharmacodynamic interactions of canagliflozin and teneligliptin, when used concomitantly in humans, have not been studied in the context of plasma GLP-1 concentration. In this study, we investigated the pharmacokinetic and pharmacodynamic interactions (specifically, GLP-1 levels) of canagliflozin and teneligliptin when used concomitantly in Japanese healthy adult male volunteers. The safety and tolerability of this drug combination were also evaluated. 2.
Patients and methods
Study design This study recruited Japanese healthy adult men aged 20 -- 50 years. Conducted as an open-label, one-way crossover study (object drug: single dose; precipitant drug: multiple doses), this study comprised two groups (Group 1 and Group 2), and each group was further categorized by two periods (Period 1 and Period 2; Figure 1). Group 1 received canagliflozin as the object drug, and Group 2 received teneligliptin as the object drug. In addition, Group 2 was evaluated for pharmacodynamic interactions (plasma concentrations of biologically active and total GLP-1). The study period comprised: Period 1, where the administration of a single oral dose of object drug on day 1 was followed by Period 2 after a washout period (at least 2.1
8
14 days); Period 2 involved continuous daily oral administration of precipitant drug from days 1 to 9. On day 7, a single dose of object drug was concomitantly administered with the precipitant drug. The object drug was administered orally 30 min before breakfast and after overnight fasting of 10 h or more. Canagliflozin and teneligliptin doses were 200 and 40 mg/day, respectively. The daily dose was established for the following reasons: canagliflozin has been developed in Japan at a dose of 100 or 200 mg/day, and the dose of teneligliptin can be increased to 40 mg/day in Japan. The FDA guidance for drug-drug interactions, moreover, recommends that the highest doses likely to be used in clinical practice be selected during the evaluation of drugs [9]. Single administration of precipitant drug is also mentioned by this FDA draft guidance as a type of study design that can be considered for drug-drug interaction studies [9]. The study protocol was reviewed and approved by the Clinical Study Review Board of the Kyushu Clinical Pharmacology Research Clinic. This study was conducted according to the ethical principles of the Declaration of Helsinki and in compliance with the Good Clinical Practice (GCP) guidelines, related laws/regulations and the protocol. Written informed consent was obtained from all volunteers prior to enrollment.
Pharmacokinetic and pharmacodynamic sampling and bioanalysis
2.2
In Group 1, for the measurement of plasma canagliflozin concentrations, blood samples were collected at 13 time points during both Periods 1 and 2 (before canagliflozin administration, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after canagliflozin administration). In addition, to confirm the level of exposure to the precipitant drug, samples were collected immediately prior to the administration of teneligliptin from days 2 to 7 in period 2. In Group 2, for the measurement of plasma teneligliptin concentrations, blood sampling was done at 13 time points for both Periods 1 and 2 (before teneligliptin administration, and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48 and 72 h after teneligliptin administration). In order to confirm the plasma concentration of the precipitant drug, blood samples were collected immediately before canagliflozin administration from days 2 to 7 in Period 2. In Group 2, for the measurement of plasma concentrations of biologically active and total GLP-1, for both Periods 1 (teneligliptin alone) and 2 (teneligliptin in combination with canagliflozin), samples were collected at seven time points (before teneligliptin administration, and 0.5, 1, 1.5, 2, 3 and 4 h after teneligliptin administration). For the measurement of plasma concentrations of canagliflozin and teneligliptin, venous blood samples were collected in EDTA-2K and sodium heparin vacuum blood collection tubes, respectively. The samples were then cooled in ice and centrifuged at 3000 rpm for 10 min. The plasma obtained
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin
Single oral dose of canagliflozin (200 mg/d)
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Group 1 Days
Single oral dose of canagliflozin (200 mg/d)
~14
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Daily oral dose of teneligliptin (40 mg/d)
Period 1
Period 2
Single oral dose of teneligliptin (40 mg/d)
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Single oral dose of teneligliptin (40 mg/d)
~14
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Daily oral dose of canagliflozin (200 mg/d)
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Figure 1. Study design.
from both tubes was aliquoted into two sample tubes and immediately stored at temperatures less than -20 C (preset temperature). For the measurement of plasma levels of active and total GLP-1, a plasma sample was collected in a blood collection tube containing an anticoagulant (EDTA-2Na) and a DPP-4 inhibitor (diprotin A) and processed using the same procedure described for the other samples. Plasma concentrations of both canagliflozin and teneligliptin were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after solid-phase extraction from plasma using a validated method, and ranged from 1 to 2000 ng/mL and 1 to 500 ng/ml, respectively, on assay. Plasma concentrations of active GLP-1 were measured by ELISA (GLP-1 [Active] ELISA kit 96-well plate; Millipore Corporation) after solid-phase extraction from plasma using an Oasis HLB 96-well plate (Waters Corporation). Plasma concentrations of total GLP-1 were determined by electrochemiluminescence (Total GLP-1 [ver.2] Assay Kit; MSD), and active and total GLP-1 levels were measured using validated methods. Plasma concentrations of canagliflozin and teneligliptin were measured by JCL Bioassay Corporation (Hyogo, Japan) and Sumika Chemical Analysis Service, Ltd. (Osaka, Japan), respectively; concentrations of active and total GLP-1 in the plasma were determined by Mitsubishi Chemical Medience Corporation (Tokyo, Japan), using a previously described procedure [10]. On the days GLP-1 was measured, breakfast for both groups and periods was standardized with regard to content and size. Statistical methods Pharmacokinetic and pharmacodynamic parameters were calculated using Phoenix WinNonlin version 6.3 (Pharsight Corporation as part of Certara). Other statistical analyses were conducted with SAS version 9.2 (SAS Institute Inc.). 2.3
The pharmacokinetic parameters for the evaluation of unchanged canagliflozin and teneligliptin in Group 1 and Group 2 were calculated by noncompartmental analysis, including the parameters: Cmax; tmax; AUC0 -- 72h, AUC0 -- 24h, AUC0 -- t, AUC0 -- ¥; t1/2; apparent terminal elimination rate constant (Kel); mean residence time (MRT0 -- ¥ ); and apparent total clearance (CL/F). For each pharmacokinetic parameter, the geometric mean ratio (GMR; geometric mean for Period 2 [object drug + precipitant drug] against the geometric mean for Period 1 [object drug alone]) and its 90% CI were calculated and compared. Among these pharmacokinetic parameters, the AUC0 -- 72h and Cmax were considered the primary pharmacokinetic parameters. The 90% CI values for the primary pharmacokinetic parameters were within the 0.8 -- 1.25 range, indicating there was no pharmacokinetic interaction [9]. Pharmacodynamic interactions were evaluated based on plasma concentrations of active and total GLP-1, for which Cmax, tmax, AUC0 -- 4h and AUC0.5 -- 4h, with 0.5 h corresponding to the time of breakfast, were calculated. The differences in the arithmetic mean between Periods 2 (teneligliptin with canagliflozin) and 1 (teneligliptin alone) and its 95% CI were evaluated to determine changes in GLP-1 levels. Pharmacokinetic interactions and GLP-1 levels for canagliflozin in combination with teneligliptin were analyzed for all subjects who completed the study; one subject who discontinued the study and for whom pharmacokinetic data and GLP-1 levels were not available was excluded from the data analysis. Safety assessments Safety was evaluated based on changes in vital signs, 12-lead ECG, laboratory values and the number of adverse events (AEs). AEs were rated by the investigators for both intensity and potential relationship (with or without a reasonable possibility) to the study drug. 2.4
3.
Results
Study subjects This study included 25 and 19 subjects in Group 1 and Group 2, respectively. Baseline characteristics (mean ± SD) of the study participants for Group 1 and Group 2, respectively, included age (27.4 ± 6.2 and 25.8 ± 3.2 years), height (171.2 ± 3.8 and 170.7 ± 4.7 cm), body weight (61.57 ± 4.54 and 62.46 ± 5.64 kg) and body mass index (BMI; 21.00 ± 1.53 and 21.45 ± 1.83 kg/m2). Pharmacokinetic and pharmacodynamic interactions were analyzed for all study subjects, with the exception of one subject in Group 2 for whom no pharmacokinetic data or GLP-1 levels were obtained after the administration of canagliflozin plus teneligliptin; the subject discontinued the study, at the discretion of the investigator, due to an AE. In total, 25 and 18 subjects from Group 1 and Group 2, respectively, were included in the analyses. 3.1
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
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Plasma concentration of CANA (ng/ml)
CANA alone (200 mg) CANA (200 mg) + TNL (40 mg) 3500 3000 2500 2000 1500 1000 500 0 0
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Figure 2. Plasma concentrations of canagliflozin (CANA) following administration of CANA alone and with teneligliptin (TNL; mean + SD; n = 25). 3.2
Pharmacokinetic evaluation
Figure 2 depicts changes in plasma concentrations of unchanged canagliflozin after administration of canagliflozin alone (200 mg) or in combination with teneligliptin (40 mg). Table 1 shows the pharmacokinetic parameters of unchanged canagliflozin. Changes in plasma levels of canagliflozin and decline from plasma over time following the administration of canagliflozin plus teneligliptin were similar to those with canagliflozin alone. The GMR (with precipitant drug/object drug alone) of the AUC0 -- 72h of unchanged canagliflozin was 0.982 (90% CI, 0.955 -- 1.011), whereas the GMR of the Cmax for canagliflozin was 0.982 (90% CI, 0.880 -- 1.095). Figure 3 shows the changes in the plasma concentration of unchanged teneligliptin with teneligliptin alone (40 mg) and teneligliptin in combination with canagliflozin (200 mg). Table 2 shows the pharmacokinetic parameters of unchanged teneligliptin. Changes in plasma levels of unchanged teneligliptin and decline from plasma over time following the administration of teneligliptin in combination with canagliflozin were similar to those with the administration of teneligliptin alone. The GMR of the AUC0 -- 72h of unchanged teneligliptin was 0.983 (90% CI, 0.940 -- 1.028). The GMR of the Cmax for teneligliptin was 0.976 (90% CI, 0.903 -- 1.056). The 90% CIs for GMRs of the primary pharmacokinetic parameters (AUC0 -- 72h and Cmax) used in the evaluation of the pharmacokinetic interaction of canagliflozin and teneligliptin were within the predefined range (0.80 -- 1.25). All other pharmacokinetic parameters evaluated showed no marked changes following the combined use of these drugs.
canagliflozin in combination versus teneligliptin alone. Explorative evaluation of the mean values of AUC0 -- 4h and AUC0.5 -- 4h of plasma levels of active GLP-1 showed that the differences in the arithmetic mean (95% CI) values of administration of teneligliptin and canagliflozin in combination and of teneligliptin alone were 2.9 (1.1 -- 4.7) pmolh/l for both. Similarly, the differences in the mean (95% CI) values of AUC0 -- 4h and AUC0.5 -- 4h of plasma total GLP-1 levels with administration of teneligliptin and canagliflozin in combination or of teneligliptin alone were 11.5 (7.8 -- 15.2) and 10.8 (7.7 -- 14.0) pmolh/l, respectively. These results indicate that the plasma concentrations (AUC0 -- 4h and AUC0.5 -- 4h) of active and total GLP-1 were higher following the administration of teneligliptin and canagliflozin in combination versus teneligliptin alone. Safety assessments Coadministration of canagliflozin with teneligliptin was well tolerated, although AEs were observed in four subjects (nasopharyngitis, 2; headache, 1; generalized erythema, 1). The subject with generalized erythema withdrew from the study. All AEs were mild and subsided over time. In the evaluation of a causal relationship of canagliflozin with the AEs, the generalized erythema in one subject was ascertained to have a ‘reasonable possibility’ of association to the study drug, whereas the other events were adjudged as being ‘without a reasonable possibility’ of association. No AEs were reported as being attributable to teneligliptin. 3.4
4. 3.3
Figure 4 shows changes in plasma concentrations of active and
total GLP-1 with the administration of teneligliptin alone (40 mg) or in combination with canagliflozin (200 mg). Table 3 shows the differences in the arithmetic mean values ([teneligliptin with canagliflozin] - teneligliptin alone) and its 95% CI for each pharmacodynamic parameter. Plasma concentrations of both active and total GLP-1 showed a notable increase following the administration of teneligliptin and 10
Discussion
Pharmacodynamic evaluation (GLP-1 levels)
This study evaluated the pharmacokinetic interactions and pharmacodynamic interactions (i.e., GLP-1 levels) with steady-state concentrations of canagliflozin and teneligliptin combination using a one-way crossover design in Japanese healthy adult male volunteers. The results demonstrated there were no noticeable changes in pharmacokinetic parameters when these drugs were coadministered. Furthermore, both doses were well tolerated. For inhibitors of SGLT2, the
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin
Table 1. Pharmacokinetic parameters for canagliflozin administered alone or in combination with teneligliptin. n
AUC0 -- 72h(ngh/ml) Cmax (ng/ml) tmax (h) AUC0 -- 24h (ngh/ml) AUC0 -- t (ngh/ml) AUC0 -- ¥ (ngh/ml) t1/2 (h) Kel (/h) MRT0 -- ¥ (h) CL/F (L/h)
Mean (SD)
25 25 25 25 25 24 24 24 24 24
GMR (90% CI)
Canagliflozin alone
Canagliflozin + teneligliptin
15681 (2538) 2125 (647) 1.6 (0.7) 12639 (2032) 15681 (2538) 16063 (2571) 14.10 (4.77) 0.0543 (0.0164) 14.47 (3.32) 12.77 (2.14)
15389 (2436) 2054 (507) 1.7 (0.5) 12480 (1997) 15389 (2436) 15796 (2558) 13.26 (3.81) 0.0559 (0.0138) 13.67 (2.90) 12.99 (2.14)
0.982 (0.955 -- 1.011) 0.982 (0.880 -- 1.095) 0.1 (-0.2 -- 0.3)* 0.988 (0.964 -- 1.012) 0.982 (0.955 -- 1.011) 0.978 (0.948 -- 1.009) 0.981 (0.920 -- 1.045) 1.020 (0.957 -- 1.087) 0.967 (0.923 -- 1.013) 1.022 (0.991 -- 1.055)
*Difference in arithmetic mean (90% CI). CL/F: Apparent total clearance; GMR: Geometric mean ratio; Kel: Apparent terminal elimination rate constant; MRT0 reach maximum plasma concentration; t1/2: Terminal half-life.
-- ¥:
Mean residence time; tmax: Time to
TNL alone (40 mg) TNL (40 mg) + CANA (200 mg) Plasma concentration of TNL (ng/ml)
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Pharmacokinetic parameter
600 500 400 300 200 100 0 0
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72
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Figure 3. Plasma concentrations of teneligliptin (TNL) following administration of TNL alone and with canagliflozin (CANA; mean + SD; n = 18).
Table 2. Pharmacokinetic parameters for teneligliptin administered alone or in combination with canagliflozin. Pharmacokinetic parameter
AUC0 -- 72h (ngh/ml) Cmax (ng/ml) tmax (h) AUC0 -- 24h (ngh/ml) AUC0 -- t (ngh/ml) AUC0 -- ¥ (ngh/ml) t1/2 (h) Kel (/h) MRT0 -- ¥ (h) CL/F (L/h)
n
18 18 18 18 18 18 18 18 18 18
Mean (SD)
GMR (90% CI)
Teneligliptin alone
Teneligliptin + canagliflozin
3494.3 (534.4) 458.3 (78.75) 1.1 (0.6) 2651.8 (337.9) 3494.3 (534.4) 3781.2 (646.3) 24.0 (6.5) 0.0306 (0.0068) 21.5 (5.5) 10.89 (1.96)
3457.0 (683.1) 444.9 (66.58) 1.1 (0.3) 2595.4 (409.5) 3457.0 (683.1) 3699.5 (743.6) 22.1 (4.8) 0.0325 (0.0059) 20.7 (4.2) 11.20 (2.08)
*Difference in arithmetic mean (90% CI). CL/F: Apparent total clearance; GMR: Geometric mean ratio; Kel: Apparent terminal elimination rate constant; MRT0 reach maximum plasma concentration; T t1/2: Terminal half-life.
efficacy of dual or triple therapy has been reported. Combinations evaluated include SGLT2 inhibitors together with metformin, insulin, sulfonylureas or thiazolidinedione as dual or triple therapy [11]. In patients with type 2 diabetes and poor
0.983 (0.940 -- 1.028) 0.976 (0.903 -- 1.056) 0.0 (-0.3 -- 0.3)* 0.975 (0.946 -- 1.005) 0.983 (0.940 -- 1.028) 0.975 (0.930 -- 1.021) 0.929 (0.816 -- 1.057) 1.076 (0.946 -- 1.224) 0.973 (0.883 -- 1.073) 1.026 (0.979 -- 1.075)
-- ¥:
Mean residence time; tmax: Time to
glycemic control, these combinations have been shown to be effective in improving various metabolic parameters (reducing HbA1c and fasting plasma glucose, improving weight loss when used along with lifestyle modification and diet control,
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
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TNL (40 mg) + CANA (200 mg)
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0 0 1 Start of the meal
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Plasma concentration of total GLP-1 (pmol/l)
Plasma concentration of active GLP-1 (pmol/l)
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TNL alone (40 mg)
15
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0 0 1 Start of the meal
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Figure 4. Plasma concentrations of active and total glucagon-like peptide-1 (GLP-1) following administration of teneligliptin (TNL) alone and with canagliflozin (CANA; mean + SD; n = 18).
Table 3. Pharmacodynamic parameters for active and total GLP-1 with teneligliptin alone or in combination with canagliflozin. Pharmacodynamic parameter
Active GLP-1 Cmax (pmol/l) tmax (h) AUC0 -- 4h (pmolh/l) AUC0.5 -- 4h (pmolh/l) Total GLP-1 Cmax (pmol/l) tmax (h) AUC0 -- 4h (pmolh/l) AUC0.5 -- 4h (pmolh/l)
n
Mean (SD)
Difference in mean (95% CI)
Teneligliptin alone
Teneligliptin + canagliflozin
18 18 18 18
4.93 (3.80) 2.0 (1.1) 10.0 (2.5) 9.6 (2.4)
5.89 (2.20) 1.6 (0.8) 12.9 (3.6) 12.5 (3.6)
0.96 (-1.03 -- 2.95) -0.4 (-0.9 -- 0.2) 2.9 (1.1 -- 4.7) 2.9 (1.1 -- 4.7)
18 18 18 18
10.45 (5.46) 2.0 (1.2) 22.8 (8.0) 21.5 (6.9)
13.42 (3.95) 1.3 (0.6) 34.3 (8.2) 32.3 (6.7)
2.98 (-0.24 -- 6.19) -0.7 (-1.4 -- 0.0) 11.5 (7.8 -- 15.2) 10.8 (7.7 -- 14.0)
GLP-1: Glucagon-like peptide-1.
and lowering systolic blood pressure) [12]. Similarly, the efficacy of DPP-4 inhibitors in combination therapy has been evaluated with similar drug classes [13]. The combination of SGLT2 inhibitors (e.g., canagliflozin) and DPP-4 inhibitors (e.g., teneligliptin) has not been evaluated in the treatment of diabetes. However, the efficacy and safety of tofogliflozin with other oral antidiabetic agents (e.g., DPP-4 inhibitors) has been evaluated in type 2 diabetes in Japan in a multicenter, open label, randomized controlled study [14]. Furthermore, the position of SGLT2 and DPP-4 inhibitors in the clinical setting and where they fit into the therapeutic pathway is yet to be determined. Although the best combination regimens are still debatable, both SGLT2 and DPP-4 inhibitors are likely to be among the most used therapeutic classes due to their excellent side-effect profiles. As both drugs are coadministered in clinical practice, the effect of systemic exposure on plasma GLP-1 levels was assessed. This study showed that plasma concentrations (AUC0 -- 4h and AUC0.5 -- 4h) of active and total GLP-1 were higher following single-dose teneligliptin with steady-state canagliflozin versus teneligliptin alone. 12
However, this difference may not be clinically relevant, and it is likely that the effect of GLP-1 is offset by the stimulating effect on glucagon [15]. Further, given that canagliflozin alone has been suggested to raise GLP-1 levels [8], the contribution of a single dose of teneligliptin with steady-state canagliflozin to the observed GLP-1 levels should be assessed with caution. These results indicate that further evaluation is required to assess the implications of this finding in diabetic populations of interest. Probenecid (a UGT inhibitor) increases the plasma concentration of canagliflozin by approximately 20%, which does not necessitate a canagliflozin dose adjustment [5]. Similarly, ketoconazole, a potent inhibitor of CYP3A4 and P-gp, can increase the plasma concentration of teneligliptin by up to approximately 50% [7]. Therefore, the extent of systemic exposure to canagliflozin and teneligliptin was not expected to increase consequent to strong drug interactions during combination therapy. Furthermore, these nonsignificant pharmacokinetic interactions at high doses in this study also allay the possibility of potential drug-drug interactions with
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
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Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin
the concomitant use of the aforementioned enzyme inhibitors. No significant interactions at high doses were observed; thus, the possibility of interactions at clinical doses (lower doses) may be ruled out. However, these results should be interpreted with caution as a single dose of object drug was concomitantly administered with the precipitant drug at a steady-state concentration. Therefore, it is unclear whether this lack of interaction would remain when both drugs are administered concomitantly at steady state. However, it is unlikely that coadministration would lead to a significant pharmacokinetic interaction considering the metabolism of the two drugs. The absence of interaction has two possible implications: i) the inhibition of CYP3A4 and FMO3 by canagliflozin is negative or weak and, thus, canagliflozin does not influence the pharmacokinetics of teneligliptin; and ii) teneligliptin has no effect on the pharmacokinetics of drugs metabolized by UGT1A9 and/or UGT2B4. These results are consistent with previous studies in healthy volunteers that report the absence of clinically relevant drug-drug interactions between the SGLT2 inhibitor, empagliflozin and the DPP-4 inhibitors, linagliptin and sitagliptin [16,17]. We used the maximum permitted teneligliptin dose (40 mg) because dose uptitration to 40 mg is allowed when the therapeutic effect is insufficient. Canagliflozin was used at a dose of 200 mg, as it was the higher dose selected for use in the Japanese confirmatory Phase III studies. These selected doses are considered reasonable to evaluate pharmacokinetic interactions [9] In principle, canagliflozin works in the renal tubule as an SGLT2 inhibitor to prevent glucose reabsorption, promoting glucose excretion in the urine [1,2]. However, oral administration of canagliflozin might transiently cause a higher canagliflozin level in the gastrointestinal tract than in the plasma. As a result, SGLT1, which is expressed in the small intestine, may be transiently inhibited, preventing the absorption of glucose following meal ingestion. Thereafter, the unabsorbed glucose reaches the lower small intestine, promoting GLP-1 secretion via the L cells [8]. However, recent findings in rats of glucose-stimulated GLP-1 secretion from perfused small intestine by SGLT1-mediated update from the lumen call this explanation into doubt [18]. This is because if GLP-1 secretion is dependent upon SGLT1 then inhibiting SGLT1 would presumably have the opposite effect to that of the mechanism just described. Nonetheless, this mechanism could still be operable because of species differences, the fact that SGLT1 inhibition by canagliflozin is considered temporary [8] and, taking the body as a whole, a possible larger contribution of GLP-1 secretion by L cells compared with that via SGLT1. In the present study, the increase in plasma GLP-1 concentration could be attributed to the enhanced postprandial secretion of GLP-1 secondary to a temporary delay of glucose absorption with canagliflozin and concurrent efficient inhibition of GLP-1 metabolism with teneligliptin, compared with that after administration of teneligliptin alone.
The limitations of this study include the fact that the secretion of GLP-1 with canagliflozin was observed only at a dose twice that of 100 mg/day, which is the clinical dose recommended in Japan. Moreover, the subjects in this study were not patients with diabetes. It is, therefore, unknown whether the plasma concentration of GLP-1 increases when both drugs are coadministered in clinical practice. Further, as both drugs were not administered concomitantly for a continuous period of time to achieve a steady-state level, the results of the pharmacokinetic and pharmacodynamic parameters may not be applicable in a real-world setting. Moreover, to determine the pharmacodynamic effect of coadministration of the drugs, baseline GLP-1/total GLP-1 levels without medication were not measured and compared to levels achieved at steady-state canagliflozin and teneligliptin+canagliflozin (both at steadystate) levels. Combination therapy with SGLT2 and DPP-4 inhibitors may become a preferred therapeutic option in the treatment of diabetes mellitus in the future; however, whether an increase in plasma GLP-1 concentration after coadministration of canagliflozin and teneligliptin, which was observed in this study, is the phenomenon generally observed with coadministration of SGLT2 and DPP-4 inhibitors at clinical doses is an issue for further research. 5.
Conclusions
We investigated the pharmacokinetic and pharmacodynamic interactions (GLP-1 levels) of canagliflozin and teneligliptin. There was no pharmacokinetic interaction observed. Moreover, we found that plasma GLP-1 concentrations are increased on administration of teneligliptin and canagliflozin in combination versus teneligliptin alone.
Acknowledgments This study was funded by Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. The authors thank Takashi Eto and Ippei Ikushima of Medical Co. LTA Hakata Clinic and Medical Co. LTA Sumida Hospital, respectively, for participating as investigators in the clinical trial. Data management and statistical analysis were undertaken by InCROM CRO Inc. Laboratory tests and measurements of active and total GLP-1 were done by the Mitsubishi Chemical Medience Corporation. The measurements of plasma concentration of canagliflozin and teneligliptin were carried out by JCL Bioassay Corporation and Sumika Chemical Analysis Service, Ltd., respectively. The Medical Co. LTA Hakata Clinic and Medical Co. LTA Sumida Hospital participated in this study as study centers.
Declaration of interest S Kinoshita and K Kondo are employees of Mitsubishi Tanabe Pharma Corporation. This study was financially supported by
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
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S. Kinoshita & K. Kondo
Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. The funding organization contributed to the study design, data collection and analysis. Manuscript writing assistance and editing services were provided by Sean Markwardt and Smitha Mathews. This work was presented, in part, as a poster at the
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Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 2011;32:515-31 Lamos EM, Younk LM, Davis SN. Canagliflozin, an inhibitor of sodiumglucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol 2013;9:763-75
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Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 2011;13:7-18 Kadowaki T, Kondo K. Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab 2013;15:810-18 InvokanaÔ [Package insert]. Janssen Pharmaceuticals, Inc. Titusville, NJ; 2014;Available from: www.invokanahcp. com/prescribing-information.pdf [Accessed on 18August 2014] Nakamaru Y, Hayashi Y, Ikegawa R, et al. Metabolism and disposition of the dipeptidyl peptidase IV inhibitor teneligliptin in humans. Xenobiotica 2014;44:242-53 This study describes the mass-balance of teneligliptin and metabolic enzymes for teneligliptin. Nakamaru Y, Hayashi Y, Sekine M, et al. Effect of ketoconazole on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor teneligliptin: an open-label study in healthy Caucasian subjects in Germany. Clin Ther 2014;36:760-9 This study suggests that teneligliptin is a substrate of p-glycoprotein.
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57th Annual Meeting of the Japan Diabetes Society, May 22, 2014, Osaka, Japan. Link: http://www2.convention.co.jp/ jds57/english/index.html. The views expressed in the submitted article are those of the authors and not an official position of the institutions or funding organization.
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;36:2154-61 This study shows that canagliflozin reduces postprandial plasma glucose and insulin by increasing the excretion of urinary glucose and delaying the appearance of oral glucose due to the inhibition of intestinal SGLT1. Guidance for industry. Drug interaction studies – Study design, data analysis, implications for dosing, and labeling recommendations. Draft Guidance. 2012. U.S. Department of Health and Human Services. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Available from: http://www.fda.gov/ downloads/drugs/guidancecompliance regulatoryinformation/guidances/ ucm292362.pdf [Accessed on 1 October 2014] Eto T, Inoue S, Kadowaki T. Effects of once-daily teneligliptin on 24-h blood glucose control and safety in Japanese patients with type 2 diabetes mellitus: a 4-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2012;14:1040-6 Clar C, Gill JA, Court R. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2012;2:5
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Kaushal S, Singh H, Thangaraju P, et al. Canagliflozin: a novel SGLT2 inhibitor for type 2 diabetes mellitus. N Am J Med Sci 2014;6:107-13
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Kishimoto M. Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes. Diabetes Metab Syndr Obes 2013;6:187-95
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Tanizawa Y, Kaku K, Araki E, et al. Long-term safety and efficacy of tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, as monotherapy or in combination with other oral antidiabetic agents in Japanese patients with type 2 diabetes mellitus: multicenter, open-label, randomized controlled trials. Expert Opin Pharmacother 2014;15:749-66
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Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodiumglucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499-508
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Brand T, Macha S, Mattheus M, et al. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, coadministered with sitagliptin in healthy volunteers. Adv Ther 2012;29:889-99
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Kuhre RE, Frost CR, Svendsen B, Holst JJ. Molecular mechanisms of glucose-stimulated GLP-1 secretion from perfused rat small intestine. Diabetes 2014. [Epub ahead of print]
Affiliation
Shuji Kinoshita†1 & Kazuoki Kondo2 MD † Author for correspondence 1 Department of Clinical Pharmacology, Development Division, Mitsubishi Tanabe Pharma Corporation, 17-10 NihonbashiKoamicho, Chuo-ku, Tokyo 103-8405, Japan Tel: +81 3 6748 7763; Fax: +81 3 3663 6449; E-mail: [email protected] 2 Development Division, Mitsubishi Tanabe Pharma Corporation, 17-10 NihonbashiKoamicho, Chuo-ku, Tokyo 103-8405, Japan
Original Research
1.
Introduction
2.
Patients and methods
3.
Results
4.
Discussion
5.
Conclusions
Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin in Japanese healthy male volunteers Shuji Kinoshita† & Kazuoki Kondo †
Department of Clinical Pharmacology, Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
Objectives: To investigate the pharmacokinetic/pharmacodynamic interactions of the antidiabetic agents canagliflozin (a sodium-glucose cotransporter-2 inhibitor) and teneligliptin (a dipeptidyl peptidase-4 inhibitor) in Japanese healthy adult men. Methods: Open-label, one-way crossover study used canagliflozin (200 mg/day p.o.) and teneligliptin (40mg/day p.o). A single dose of object drug (either canagliflozin or teneligliptin) was administered on day 1 followed by washout and continuous administration of precipitant drug (days 1 -- 9). Both drugs were concomitantly administered on day 7. Results: No changes in AUC0 -- 72h and Cmax were observed for canagliflozin +teneligliptin versus monotherapy; geometric mean ratios for AUC0 -- 72h and Cmax were 0.982 and 0.982 for the plasma concentration of canagliflozin and 0.983 and 0.976 for the plasma concentration of teneligliptin, respectively. Plasma concentrations of active and total glucagon-like peptide-1 (GLP-1) increased with canagliflozin+teneligliptin versus teneligliptin alone. Mean AUC0.5 -- 4h increased post-meal, on combination therapy, from 9.6 to 12.5 pmolh/l (active GLP-1) and from 21.5 to 32.3 pmolh/l (total GLP-1). Adverse events developed in four subjects; all were mild and resolved but one subject withdrew due to generalized erythema. Conclusions: GLP-1 levels increased with the canagliflozin+teneligliptin combination, and no PK interaction was observed. This combination may show favorable antidiabetic effects without increasing systemic exposure. Keywords: canagliflozin, DPP-4 inhibitor, drug-drug interaction, SGLT2 inhibitor, teneligliptin Expert Opin. Drug Metab. Toxicol. (2015) 11(1):7-14
1.
Introduction
Canagliflozin, a selective sodium-glucose cotransporter (SGLT)-2 inhibitor, is a novel antidiabetic drug that lowers blood glucose levels via a new mechanism of action, whereby it inhibits glucose reabsorption in the renal tubule, thus promoting glucose excretion into the urine [1,2]. Teneligliptin, on the other hand, increases circulating plasma levels of biologically active glucagon-like peptide-1 (GLP-1) by inhibiting the DPP-4 enzyme and, thereby, lowers blood glucose by promoting insulin secretion and suppressing glucagon secretion in a blood-glucose-dependent manner [3,4]. Both canagliflozin and teneligliptin are considered effective as treatments for type 2 diabetes mellitus, despite differences in their therapeutic targets and mechanisms of action. Therefore, coadministration of canagliflozin and 10.1517/17425255.2015.982531 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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S. Kinoshita & K. Kondo
teneligliptin is expected to achieve a satisfactory therapeutic effect in patients who have responded poorly to either agent alone. We expect that combination therapy with these two agents would enhance the effects of conventional therapy, with the possibility of pharmacodynamic interactions that could potentiate therapeutic effects following the addition of a new drug. However, pharmacokinetic interactions pose a concern for the use of combination therapy. Following oral administration and absorption in humans, canagliflozin is mainly eliminated by the uridine diphosphate glucuronosyltransferase (UGT) 1A9 and UGT2B4 metabolic enzymes. CYP3A4 is partly involved in the metabolism of canagliflozin [5]. In addition, canagliflozin is a substrate of the transporters p-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) [5]. For teneligliptin, after oral administration and absorption in humans, approximately 66 -- 80% of the drug is eliminated by metabolism and approximately 20 -- 34% undergoes urinary excretion via the kidneys [6]. CYP3A4 and flavin-containing monooxygenase (FMO3) are the main enzymes involved in the metabolism of teneligliptin [6], which also behaves as a substrate for P-gp [7]. Although these pharmacokinetic properties of canagliflozin and teneligliptin have been determined, the possibility and extent of pharmacokinetic interactions between canagliflozin and teneligliptin, when administered concomitantly, have not been investigated. With regard to pharmacodynamic interactions, a high dose of canagliflozin (300 mg) was reported to increase plasma GLP-1 levels when administered in the absence of a DPP-4 inhibitor to healthy adults [8]. However, the pharmacodynamic interactions of canagliflozin and teneligliptin, when used concomitantly in humans, have not been studied in the context of plasma GLP-1 concentration. In this study, we investigated the pharmacokinetic and pharmacodynamic interactions (specifically, GLP-1 levels) of canagliflozin and teneligliptin when used concomitantly in Japanese healthy adult male volunteers. The safety and tolerability of this drug combination were also evaluated. 2.
Patients and methods
Study design This study recruited Japanese healthy adult men aged 20 -- 50 years. Conducted as an open-label, one-way crossover study (object drug: single dose; precipitant drug: multiple doses), this study comprised two groups (Group 1 and Group 2), and each group was further categorized by two periods (Period 1 and Period 2; Figure 1). Group 1 received canagliflozin as the object drug, and Group 2 received teneligliptin as the object drug. In addition, Group 2 was evaluated for pharmacodynamic interactions (plasma concentrations of biologically active and total GLP-1). The study period comprised: Period 1, where the administration of a single oral dose of object drug on day 1 was followed by Period 2 after a washout period (at least 2.1
8
14 days); Period 2 involved continuous daily oral administration of precipitant drug from days 1 to 9. On day 7, a single dose of object drug was concomitantly administered with the precipitant drug. The object drug was administered orally 30 min before breakfast and after overnight fasting of 10 h or more. Canagliflozin and teneligliptin doses were 200 and 40 mg/day, respectively. The daily dose was established for the following reasons: canagliflozin has been developed in Japan at a dose of 100 or 200 mg/day, and the dose of teneligliptin can be increased to 40 mg/day in Japan. The FDA guidance for drug-drug interactions, moreover, recommends that the highest doses likely to be used in clinical practice be selected during the evaluation of drugs [9]. Single administration of precipitant drug is also mentioned by this FDA draft guidance as a type of study design that can be considered for drug-drug interaction studies [9]. The study protocol was reviewed and approved by the Clinical Study Review Board of the Kyushu Clinical Pharmacology Research Clinic. This study was conducted according to the ethical principles of the Declaration of Helsinki and in compliance with the Good Clinical Practice (GCP) guidelines, related laws/regulations and the protocol. Written informed consent was obtained from all volunteers prior to enrollment.
Pharmacokinetic and pharmacodynamic sampling and bioanalysis
2.2
In Group 1, for the measurement of plasma canagliflozin concentrations, blood samples were collected at 13 time points during both Periods 1 and 2 (before canagliflozin administration, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after canagliflozin administration). In addition, to confirm the level of exposure to the precipitant drug, samples were collected immediately prior to the administration of teneligliptin from days 2 to 7 in period 2. In Group 2, for the measurement of plasma teneligliptin concentrations, blood sampling was done at 13 time points for both Periods 1 and 2 (before teneligliptin administration, and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48 and 72 h after teneligliptin administration). In order to confirm the plasma concentration of the precipitant drug, blood samples were collected immediately before canagliflozin administration from days 2 to 7 in Period 2. In Group 2, for the measurement of plasma concentrations of biologically active and total GLP-1, for both Periods 1 (teneligliptin alone) and 2 (teneligliptin in combination with canagliflozin), samples were collected at seven time points (before teneligliptin administration, and 0.5, 1, 1.5, 2, 3 and 4 h after teneligliptin administration). For the measurement of plasma concentrations of canagliflozin and teneligliptin, venous blood samples were collected in EDTA-2K and sodium heparin vacuum blood collection tubes, respectively. The samples were then cooled in ice and centrifuged at 3000 rpm for 10 min. The plasma obtained
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin
Single oral dose of canagliflozin (200 mg/d)
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Group 1 Days
Single oral dose of canagliflozin (200 mg/d)
~14
1
2
3
4
5
6
7
8
9
Washout period
Daily oral dose of teneligliptin (40 mg/d)
Period 1
Period 2
Single oral dose of teneligliptin (40 mg/d)
Group 2 Days
Single oral dose of teneligliptin (40 mg/d)
~14
1
2
3
4
5
6
7
8
9
Washout period
Daily oral dose of canagliflozin (200 mg/d)
Period 1
Period 2
Figure 1. Study design.
from both tubes was aliquoted into two sample tubes and immediately stored at temperatures less than -20 C (preset temperature). For the measurement of plasma levels of active and total GLP-1, a plasma sample was collected in a blood collection tube containing an anticoagulant (EDTA-2Na) and a DPP-4 inhibitor (diprotin A) and processed using the same procedure described for the other samples. Plasma concentrations of both canagliflozin and teneligliptin were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after solid-phase extraction from plasma using a validated method, and ranged from 1 to 2000 ng/mL and 1 to 500 ng/ml, respectively, on assay. Plasma concentrations of active GLP-1 were measured by ELISA (GLP-1 [Active] ELISA kit 96-well plate; Millipore Corporation) after solid-phase extraction from plasma using an Oasis HLB 96-well plate (Waters Corporation). Plasma concentrations of total GLP-1 were determined by electrochemiluminescence (Total GLP-1 [ver.2] Assay Kit; MSD), and active and total GLP-1 levels were measured using validated methods. Plasma concentrations of canagliflozin and teneligliptin were measured by JCL Bioassay Corporation (Hyogo, Japan) and Sumika Chemical Analysis Service, Ltd. (Osaka, Japan), respectively; concentrations of active and total GLP-1 in the plasma were determined by Mitsubishi Chemical Medience Corporation (Tokyo, Japan), using a previously described procedure [10]. On the days GLP-1 was measured, breakfast for both groups and periods was standardized with regard to content and size. Statistical methods Pharmacokinetic and pharmacodynamic parameters were calculated using Phoenix WinNonlin version 6.3 (Pharsight Corporation as part of Certara). Other statistical analyses were conducted with SAS version 9.2 (SAS Institute Inc.). 2.3
The pharmacokinetic parameters for the evaluation of unchanged canagliflozin and teneligliptin in Group 1 and Group 2 were calculated by noncompartmental analysis, including the parameters: Cmax; tmax; AUC0 -- 72h, AUC0 -- 24h, AUC0 -- t, AUC0 -- ¥; t1/2; apparent terminal elimination rate constant (Kel); mean residence time (MRT0 -- ¥ ); and apparent total clearance (CL/F). For each pharmacokinetic parameter, the geometric mean ratio (GMR; geometric mean for Period 2 [object drug + precipitant drug] against the geometric mean for Period 1 [object drug alone]) and its 90% CI were calculated and compared. Among these pharmacokinetic parameters, the AUC0 -- 72h and Cmax were considered the primary pharmacokinetic parameters. The 90% CI values for the primary pharmacokinetic parameters were within the 0.8 -- 1.25 range, indicating there was no pharmacokinetic interaction [9]. Pharmacodynamic interactions were evaluated based on plasma concentrations of active and total GLP-1, for which Cmax, tmax, AUC0 -- 4h and AUC0.5 -- 4h, with 0.5 h corresponding to the time of breakfast, were calculated. The differences in the arithmetic mean between Periods 2 (teneligliptin with canagliflozin) and 1 (teneligliptin alone) and its 95% CI were evaluated to determine changes in GLP-1 levels. Pharmacokinetic interactions and GLP-1 levels for canagliflozin in combination with teneligliptin were analyzed for all subjects who completed the study; one subject who discontinued the study and for whom pharmacokinetic data and GLP-1 levels were not available was excluded from the data analysis. Safety assessments Safety was evaluated based on changes in vital signs, 12-lead ECG, laboratory values and the number of adverse events (AEs). AEs were rated by the investigators for both intensity and potential relationship (with or without a reasonable possibility) to the study drug. 2.4
3.
Results
Study subjects This study included 25 and 19 subjects in Group 1 and Group 2, respectively. Baseline characteristics (mean ± SD) of the study participants for Group 1 and Group 2, respectively, included age (27.4 ± 6.2 and 25.8 ± 3.2 years), height (171.2 ± 3.8 and 170.7 ± 4.7 cm), body weight (61.57 ± 4.54 and 62.46 ± 5.64 kg) and body mass index (BMI; 21.00 ± 1.53 and 21.45 ± 1.83 kg/m2). Pharmacokinetic and pharmacodynamic interactions were analyzed for all study subjects, with the exception of one subject in Group 2 for whom no pharmacokinetic data or GLP-1 levels were obtained after the administration of canagliflozin plus teneligliptin; the subject discontinued the study, at the discretion of the investigator, due to an AE. In total, 25 and 18 subjects from Group 1 and Group 2, respectively, were included in the analyses. 3.1
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S. Kinoshita & K. Kondo
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Plasma concentration of CANA (ng/ml)
CANA alone (200 mg) CANA (200 mg) + TNL (40 mg) 3500 3000 2500 2000 1500 1000 500 0 0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Time (h)
Figure 2. Plasma concentrations of canagliflozin (CANA) following administration of CANA alone and with teneligliptin (TNL; mean + SD; n = 25). 3.2
Pharmacokinetic evaluation
Figure 2 depicts changes in plasma concentrations of unchanged canagliflozin after administration of canagliflozin alone (200 mg) or in combination with teneligliptin (40 mg). Table 1 shows the pharmacokinetic parameters of unchanged canagliflozin. Changes in plasma levels of canagliflozin and decline from plasma over time following the administration of canagliflozin plus teneligliptin were similar to those with canagliflozin alone. The GMR (with precipitant drug/object drug alone) of the AUC0 -- 72h of unchanged canagliflozin was 0.982 (90% CI, 0.955 -- 1.011), whereas the GMR of the Cmax for canagliflozin was 0.982 (90% CI, 0.880 -- 1.095). Figure 3 shows the changes in the plasma concentration of unchanged teneligliptin with teneligliptin alone (40 mg) and teneligliptin in combination with canagliflozin (200 mg). Table 2 shows the pharmacokinetic parameters of unchanged teneligliptin. Changes in plasma levels of unchanged teneligliptin and decline from plasma over time following the administration of teneligliptin in combination with canagliflozin were similar to those with the administration of teneligliptin alone. The GMR of the AUC0 -- 72h of unchanged teneligliptin was 0.983 (90% CI, 0.940 -- 1.028). The GMR of the Cmax for teneligliptin was 0.976 (90% CI, 0.903 -- 1.056). The 90% CIs for GMRs of the primary pharmacokinetic parameters (AUC0 -- 72h and Cmax) used in the evaluation of the pharmacokinetic interaction of canagliflozin and teneligliptin were within the predefined range (0.80 -- 1.25). All other pharmacokinetic parameters evaluated showed no marked changes following the combined use of these drugs.
canagliflozin in combination versus teneligliptin alone. Explorative evaluation of the mean values of AUC0 -- 4h and AUC0.5 -- 4h of plasma levels of active GLP-1 showed that the differences in the arithmetic mean (95% CI) values of administration of teneligliptin and canagliflozin in combination and of teneligliptin alone were 2.9 (1.1 -- 4.7) pmolh/l for both. Similarly, the differences in the mean (95% CI) values of AUC0 -- 4h and AUC0.5 -- 4h of plasma total GLP-1 levels with administration of teneligliptin and canagliflozin in combination or of teneligliptin alone were 11.5 (7.8 -- 15.2) and 10.8 (7.7 -- 14.0) pmolh/l, respectively. These results indicate that the plasma concentrations (AUC0 -- 4h and AUC0.5 -- 4h) of active and total GLP-1 were higher following the administration of teneligliptin and canagliflozin in combination versus teneligliptin alone. Safety assessments Coadministration of canagliflozin with teneligliptin was well tolerated, although AEs were observed in four subjects (nasopharyngitis, 2; headache, 1; generalized erythema, 1). The subject with generalized erythema withdrew from the study. All AEs were mild and subsided over time. In the evaluation of a causal relationship of canagliflozin with the AEs, the generalized erythema in one subject was ascertained to have a ‘reasonable possibility’ of association to the study drug, whereas the other events were adjudged as being ‘without a reasonable possibility’ of association. No AEs were reported as being attributable to teneligliptin. 3.4
4. 3.3
Figure 4 shows changes in plasma concentrations of active and
total GLP-1 with the administration of teneligliptin alone (40 mg) or in combination with canagliflozin (200 mg). Table 3 shows the differences in the arithmetic mean values ([teneligliptin with canagliflozin] - teneligliptin alone) and its 95% CI for each pharmacodynamic parameter. Plasma concentrations of both active and total GLP-1 showed a notable increase following the administration of teneligliptin and 10
Discussion
Pharmacodynamic evaluation (GLP-1 levels)
This study evaluated the pharmacokinetic interactions and pharmacodynamic interactions (i.e., GLP-1 levels) with steady-state concentrations of canagliflozin and teneligliptin combination using a one-way crossover design in Japanese healthy adult male volunteers. The results demonstrated there were no noticeable changes in pharmacokinetic parameters when these drugs were coadministered. Furthermore, both doses were well tolerated. For inhibitors of SGLT2, the
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin
Table 1. Pharmacokinetic parameters for canagliflozin administered alone or in combination with teneligliptin. n
AUC0 -- 72h(ngh/ml) Cmax (ng/ml) tmax (h) AUC0 -- 24h (ngh/ml) AUC0 -- t (ngh/ml) AUC0 -- ¥ (ngh/ml) t1/2 (h) Kel (/h) MRT0 -- ¥ (h) CL/F (L/h)
Mean (SD)
25 25 25 25 25 24 24 24 24 24
GMR (90% CI)
Canagliflozin alone
Canagliflozin + teneligliptin
15681 (2538) 2125 (647) 1.6 (0.7) 12639 (2032) 15681 (2538) 16063 (2571) 14.10 (4.77) 0.0543 (0.0164) 14.47 (3.32) 12.77 (2.14)
15389 (2436) 2054 (507) 1.7 (0.5) 12480 (1997) 15389 (2436) 15796 (2558) 13.26 (3.81) 0.0559 (0.0138) 13.67 (2.90) 12.99 (2.14)
0.982 (0.955 -- 1.011) 0.982 (0.880 -- 1.095) 0.1 (-0.2 -- 0.3)* 0.988 (0.964 -- 1.012) 0.982 (0.955 -- 1.011) 0.978 (0.948 -- 1.009) 0.981 (0.920 -- 1.045) 1.020 (0.957 -- 1.087) 0.967 (0.923 -- 1.013) 1.022 (0.991 -- 1.055)
*Difference in arithmetic mean (90% CI). CL/F: Apparent total clearance; GMR: Geometric mean ratio; Kel: Apparent terminal elimination rate constant; MRT0 reach maximum plasma concentration; t1/2: Terminal half-life.
-- ¥:
Mean residence time; tmax: Time to
TNL alone (40 mg) TNL (40 mg) + CANA (200 mg) Plasma concentration of TNL (ng/ml)
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Pharmacokinetic parameter
600 500 400 300 200 100 0 0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Time (h)
Figure 3. Plasma concentrations of teneligliptin (TNL) following administration of TNL alone and with canagliflozin (CANA; mean + SD; n = 18).
Table 2. Pharmacokinetic parameters for teneligliptin administered alone or in combination with canagliflozin. Pharmacokinetic parameter
AUC0 -- 72h (ngh/ml) Cmax (ng/ml) tmax (h) AUC0 -- 24h (ngh/ml) AUC0 -- t (ngh/ml) AUC0 -- ¥ (ngh/ml) t1/2 (h) Kel (/h) MRT0 -- ¥ (h) CL/F (L/h)
n
18 18 18 18 18 18 18 18 18 18
Mean (SD)
GMR (90% CI)
Teneligliptin alone
Teneligliptin + canagliflozin
3494.3 (534.4) 458.3 (78.75) 1.1 (0.6) 2651.8 (337.9) 3494.3 (534.4) 3781.2 (646.3) 24.0 (6.5) 0.0306 (0.0068) 21.5 (5.5) 10.89 (1.96)
3457.0 (683.1) 444.9 (66.58) 1.1 (0.3) 2595.4 (409.5) 3457.0 (683.1) 3699.5 (743.6) 22.1 (4.8) 0.0325 (0.0059) 20.7 (4.2) 11.20 (2.08)
*Difference in arithmetic mean (90% CI). CL/F: Apparent total clearance; GMR: Geometric mean ratio; Kel: Apparent terminal elimination rate constant; MRT0 reach maximum plasma concentration; T t1/2: Terminal half-life.
efficacy of dual or triple therapy has been reported. Combinations evaluated include SGLT2 inhibitors together with metformin, insulin, sulfonylureas or thiazolidinedione as dual or triple therapy [11]. In patients with type 2 diabetes and poor
0.983 (0.940 -- 1.028) 0.976 (0.903 -- 1.056) 0.0 (-0.3 -- 0.3)* 0.975 (0.946 -- 1.005) 0.983 (0.940 -- 1.028) 0.975 (0.930 -- 1.021) 0.929 (0.816 -- 1.057) 1.076 (0.946 -- 1.224) 0.973 (0.883 -- 1.073) 1.026 (0.979 -- 1.075)
-- ¥:
Mean residence time; tmax: Time to
glycemic control, these combinations have been shown to be effective in improving various metabolic parameters (reducing HbA1c and fasting plasma glucose, improving weight loss when used along with lifestyle modification and diet control,
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S. Kinoshita & K. Kondo
TNL (40 mg) + CANA (200 mg)
15
10
5
0 0 1 Start of the meal
2
3
4
Time (h)
Plasma concentration of total GLP-1 (pmol/l)
Plasma concentration of active GLP-1 (pmol/l)
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TNL alone (40 mg)
15
10
5
0 0 1 Start of the meal
2
3
4
Time (h)
Figure 4. Plasma concentrations of active and total glucagon-like peptide-1 (GLP-1) following administration of teneligliptin (TNL) alone and with canagliflozin (CANA; mean + SD; n = 18).
Table 3. Pharmacodynamic parameters for active and total GLP-1 with teneligliptin alone or in combination with canagliflozin. Pharmacodynamic parameter
Active GLP-1 Cmax (pmol/l) tmax (h) AUC0 -- 4h (pmolh/l) AUC0.5 -- 4h (pmolh/l) Total GLP-1 Cmax (pmol/l) tmax (h) AUC0 -- 4h (pmolh/l) AUC0.5 -- 4h (pmolh/l)
n
Mean (SD)
Difference in mean (95% CI)
Teneligliptin alone
Teneligliptin + canagliflozin
18 18 18 18
4.93 (3.80) 2.0 (1.1) 10.0 (2.5) 9.6 (2.4)
5.89 (2.20) 1.6 (0.8) 12.9 (3.6) 12.5 (3.6)
0.96 (-1.03 -- 2.95) -0.4 (-0.9 -- 0.2) 2.9 (1.1 -- 4.7) 2.9 (1.1 -- 4.7)
18 18 18 18
10.45 (5.46) 2.0 (1.2) 22.8 (8.0) 21.5 (6.9)
13.42 (3.95) 1.3 (0.6) 34.3 (8.2) 32.3 (6.7)
2.98 (-0.24 -- 6.19) -0.7 (-1.4 -- 0.0) 11.5 (7.8 -- 15.2) 10.8 (7.7 -- 14.0)
GLP-1: Glucagon-like peptide-1.
and lowering systolic blood pressure) [12]. Similarly, the efficacy of DPP-4 inhibitors in combination therapy has been evaluated with similar drug classes [13]. The combination of SGLT2 inhibitors (e.g., canagliflozin) and DPP-4 inhibitors (e.g., teneligliptin) has not been evaluated in the treatment of diabetes. However, the efficacy and safety of tofogliflozin with other oral antidiabetic agents (e.g., DPP-4 inhibitors) has been evaluated in type 2 diabetes in Japan in a multicenter, open label, randomized controlled study [14]. Furthermore, the position of SGLT2 and DPP-4 inhibitors in the clinical setting and where they fit into the therapeutic pathway is yet to be determined. Although the best combination regimens are still debatable, both SGLT2 and DPP-4 inhibitors are likely to be among the most used therapeutic classes due to their excellent side-effect profiles. As both drugs are coadministered in clinical practice, the effect of systemic exposure on plasma GLP-1 levels was assessed. This study showed that plasma concentrations (AUC0 -- 4h and AUC0.5 -- 4h) of active and total GLP-1 were higher following single-dose teneligliptin with steady-state canagliflozin versus teneligliptin alone. 12
However, this difference may not be clinically relevant, and it is likely that the effect of GLP-1 is offset by the stimulating effect on glucagon [15]. Further, given that canagliflozin alone has been suggested to raise GLP-1 levels [8], the contribution of a single dose of teneligliptin with steady-state canagliflozin to the observed GLP-1 levels should be assessed with caution. These results indicate that further evaluation is required to assess the implications of this finding in diabetic populations of interest. Probenecid (a UGT inhibitor) increases the plasma concentration of canagliflozin by approximately 20%, which does not necessitate a canagliflozin dose adjustment [5]. Similarly, ketoconazole, a potent inhibitor of CYP3A4 and P-gp, can increase the plasma concentration of teneligliptin by up to approximately 50% [7]. Therefore, the extent of systemic exposure to canagliflozin and teneligliptin was not expected to increase consequent to strong drug interactions during combination therapy. Furthermore, these nonsignificant pharmacokinetic interactions at high doses in this study also allay the possibility of potential drug-drug interactions with
Expert Opin. Drug Metab. Toxicol. (2015) 11(1)
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Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin
the concomitant use of the aforementioned enzyme inhibitors. No significant interactions at high doses were observed; thus, the possibility of interactions at clinical doses (lower doses) may be ruled out. However, these results should be interpreted with caution as a single dose of object drug was concomitantly administered with the precipitant drug at a steady-state concentration. Therefore, it is unclear whether this lack of interaction would remain when both drugs are administered concomitantly at steady state. However, it is unlikely that coadministration would lead to a significant pharmacokinetic interaction considering the metabolism of the two drugs. The absence of interaction has two possible implications: i) the inhibition of CYP3A4 and FMO3 by canagliflozin is negative or weak and, thus, canagliflozin does not influence the pharmacokinetics of teneligliptin; and ii) teneligliptin has no effect on the pharmacokinetics of drugs metabolized by UGT1A9 and/or UGT2B4. These results are consistent with previous studies in healthy volunteers that report the absence of clinically relevant drug-drug interactions between the SGLT2 inhibitor, empagliflozin and the DPP-4 inhibitors, linagliptin and sitagliptin [16,17]. We used the maximum permitted teneligliptin dose (40 mg) because dose uptitration to 40 mg is allowed when the therapeutic effect is insufficient. Canagliflozin was used at a dose of 200 mg, as it was the higher dose selected for use in the Japanese confirmatory Phase III studies. These selected doses are considered reasonable to evaluate pharmacokinetic interactions [9] In principle, canagliflozin works in the renal tubule as an SGLT2 inhibitor to prevent glucose reabsorption, promoting glucose excretion in the urine [1,2]. However, oral administration of canagliflozin might transiently cause a higher canagliflozin level in the gastrointestinal tract than in the plasma. As a result, SGLT1, which is expressed in the small intestine, may be transiently inhibited, preventing the absorption of glucose following meal ingestion. Thereafter, the unabsorbed glucose reaches the lower small intestine, promoting GLP-1 secretion via the L cells [8]. However, recent findings in rats of glucose-stimulated GLP-1 secretion from perfused small intestine by SGLT1-mediated update from the lumen call this explanation into doubt [18]. This is because if GLP-1 secretion is dependent upon SGLT1 then inhibiting SGLT1 would presumably have the opposite effect to that of the mechanism just described. Nonetheless, this mechanism could still be operable because of species differences, the fact that SGLT1 inhibition by canagliflozin is considered temporary [8] and, taking the body as a whole, a possible larger contribution of GLP-1 secretion by L cells compared with that via SGLT1. In the present study, the increase in plasma GLP-1 concentration could be attributed to the enhanced postprandial secretion of GLP-1 secondary to a temporary delay of glucose absorption with canagliflozin and concurrent efficient inhibition of GLP-1 metabolism with teneligliptin, compared with that after administration of teneligliptin alone.
The limitations of this study include the fact that the secretion of GLP-1 with canagliflozin was observed only at a dose twice that of 100 mg/day, which is the clinical dose recommended in Japan. Moreover, the subjects in this study were not patients with diabetes. It is, therefore, unknown whether the plasma concentration of GLP-1 increases when both drugs are coadministered in clinical practice. Further, as both drugs were not administered concomitantly for a continuous period of time to achieve a steady-state level, the results of the pharmacokinetic and pharmacodynamic parameters may not be applicable in a real-world setting. Moreover, to determine the pharmacodynamic effect of coadministration of the drugs, baseline GLP-1/total GLP-1 levels without medication were not measured and compared to levels achieved at steady-state canagliflozin and teneligliptin+canagliflozin (both at steadystate) levels. Combination therapy with SGLT2 and DPP-4 inhibitors may become a preferred therapeutic option in the treatment of diabetes mellitus in the future; however, whether an increase in plasma GLP-1 concentration after coadministration of canagliflozin and teneligliptin, which was observed in this study, is the phenomenon generally observed with coadministration of SGLT2 and DPP-4 inhibitors at clinical doses is an issue for further research. 5.
Conclusions
We investigated the pharmacokinetic and pharmacodynamic interactions (GLP-1 levels) of canagliflozin and teneligliptin. There was no pharmacokinetic interaction observed. Moreover, we found that plasma GLP-1 concentrations are increased on administration of teneligliptin and canagliflozin in combination versus teneligliptin alone.
Acknowledgments This study was funded by Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. The authors thank Takashi Eto and Ippei Ikushima of Medical Co. LTA Hakata Clinic and Medical Co. LTA Sumida Hospital, respectively, for participating as investigators in the clinical trial. Data management and statistical analysis were undertaken by InCROM CRO Inc. Laboratory tests and measurements of active and total GLP-1 were done by the Mitsubishi Chemical Medience Corporation. The measurements of plasma concentration of canagliflozin and teneligliptin were carried out by JCL Bioassay Corporation and Sumika Chemical Analysis Service, Ltd., respectively. The Medical Co. LTA Hakata Clinic and Medical Co. LTA Sumida Hospital participated in this study as study centers.
Declaration of interest S Kinoshita and K Kondo are employees of Mitsubishi Tanabe Pharma Corporation. This study was financially supported by
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Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. The funding organization contributed to the study design, data collection and analysis. Manuscript writing assistance and editing services were provided by Sean Markwardt and Smitha Mathews. This work was presented, in part, as a poster at the
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Affiliation
Shuji Kinoshita†1 & Kazuoki Kondo2 MD † Author for correspondence 1 Department of Clinical Pharmacology, Development Division, Mitsubishi Tanabe Pharma Corporation, 17-10 NihonbashiKoamicho, Chuo-ku, Tokyo 103-8405, Japan Tel: +81 3 6748 7763; Fax: +81 3 3663 6449; E-mail: [email protected] 2 Development Division, Mitsubishi Tanabe Pharma Corporation, 17-10 NihonbashiKoamicho, Chuo-ku, Tokyo 103-8405, Japan
