Canagliflozin Hemihydrate
Canagliflozin was approved by the U.S. Food and Drug Administration (FDA) on Mar 29, 2013, then approved by European Medicine Agency (EMA) on Nov 15, 2013, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jul 4, 2014. It was originally developed by Mitsubishi Tanabe Pharma. Janssen pharmaceuticals acquired the license in US and EU in 2012. In Japan this drug is manufactured and marketed by Mitsubishi and co-promoted in conjunction with Daiichi Sankyo. It is marketed as Invokana®.
Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney (SGLT1 being responsible for the remaining 10%). Anagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE). It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Invokana® is available as film-coated, tablet for oral use, containing 100 mg or 300 mg of free Canagliflozin. The recommended starting dose is 100 mg once daily, taken before the first meal of the day.
Update Date：2015-11-26
- Drug Name：
- Canagliflozin Hemihydrate
- Research Code：
- JNJ-24831754; TA-7284; R-600348
- Trade Name：
- Invokana® / Canaglu®
- MOA：
- Sodium-glucose cotransporter 2 (SGLT2) inhibitor
- Indication：
- Type 2 diabetes
- Status：
- Approved
- Company：
- Mitsubishi Tanabe (Originator) , Daiichi Sankyo,Janssen
- Sales：
- ATC Code：
- A10BX11
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-03-29 | Marketing approval | Invokana | Type 2 diabetes | Tablet, Film coated | Eq. 100 mg/300 mg Canagliflozin | Janssen |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-11-15 | Marketing approval | Invokana | Type 2 diabetes | Tablet, Film coated | 100 mg/300 mg | Janssen |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-07-04 | Marketing approval | Canaglu | Type 2 diabetes | Tablet, Film coated | 100 mg | Mitsubishi Tanabe, Daiichi Sankyo |
Update Date：2015-09-16
|
Molecular Weight | 453.53 | ||||||||||||
| Formula | C24H25FO5S•1/2 H2O | |||||||||||||
| CAS No. |
842133-18-0 (Canagliflozin); 928672-86-0 (Canagliflozin Hemihydrate); |
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| Chemical Name | (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate | |||||||||||||
| Canagliflozin （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-08-31
Update Date：2015-11-25
Update Date：2016-06-07
Mechanism of Action
Canagliflozin is an orally active inhibitor of sodium-glucose co-transporter-2 (SGLT2), the low-affinity/high-capacity SGLT2 transporter in the proximal renal tubule reabsorbs the majority of glucose filtered by the renal glomerulus.
Canagliflozin selectively inhibited SGLT2 and SGLT1 (IC50 = 4.2 nM and 663 nM). The inhibition of SGLT2 was expected to decrease renal glucose re-absorption, and thereby increase urinary glucose excretion (UGE) and lower plasma glucose (PG) in patients with type 2 diabetes.
No significant inhibition in a screen against 50 receptors and transporters at 1 μM canagliflozin hydrate.
In Vivo Efficacy
In normal animal:
● Significantly inhibited renal glucose reabsorption and UGE at 1 mg/kg in SD rats.
● Significantly increased UGE at 0.3 mg/kg in dogs, and at 10 mg/kg in C57BL/6J mice (ED50 = 8.174 mg/kg).
Single-dose in ZDF diabetic rats: Significantly decreased AUC_iRGR0-6 h at 3 mg/kg, AUC_PG0-6 h at 0.3 mg/kg, AUC_PG0-24 h at 1 mg/kg.
Chronic treatment in ZDF rats:
● Significantly decreased blood glucose at 3 mg/kg/day after day 9.
● Significantly decreased HbA1c from 11.5 to 7.1% at 3 mg/kg/day after 4 weeks treatment.
● Significantly decreased AUC_BG and increased AUC_Ins at 3 mg/kg/day in OGTT on day 24.
● Significantly increased body weight gain at 3 mg/kg/day after day 11.
Update Date：2016-06-07
Absorption of Canagliflozin
Exhibited a linear pharmacokinetics in humans following oral dosing. The increases in Cmax and AUC appeared to be dose-proportional in the dose range of 50 to 300 mg canagliflozin.
Had a high bioavailability in mice (109%-125%), dogs (63%-67.6%), and humans (65%), but moderate in rats (34.1%-34.9%) and monkeys (48.8%).
Was absorbed rapidly in humans (Tmax = 1.5 h), mice (Tmax = 1 h), dogs (Tmax = 2-2.8 h), but slowly in rats (Tmax = 5 h) and monkeys (Tmax = 3.5 h).
Showed half-life of 6.88 h in humans, close to those in rats (6.27-7.47 h), dogs (6.63-6.83 h) and monkeys (6.06 h), but longer than that in mice (2.99-3.27 h), after intravenous administration.
Had a low clearance in rats (161-231 mL/h/kg), mice (476-642 mL/h/kg), dogs (72.0-88.3 mL/h/kg), monkeys (280 mL/h/kg) and humans (12.2 L/h), compared to liver blood flow, after intravenous administration.
Exhibited an extensive distribution in rats, mice, dogs, monkeys and humans, with the apparent volume of distribution of 1908-2466 mL/kg, 1610-1780 mL/kg, 596-755 mL/kg, 1980 mL/kg and 119 L, respectively, after intravenous administration.
Showed a moderate permeability, with a Papp(A→B) of 4.1-8.6 × 10-6 cm/s in Caco-2 cell monolayer model.
Distribution of Canagliflozin
Exhibited high plasma protein binding in humans (98.3%), rats (>98.5%), mice (>98.9%), dogs (>98.8%), rabbits (98.2%) and monkeys (>98.1%). In addition, canagliflozin was mainly bound to human serum albumin.
Had a Cb:Cp ratio of 0.77-0.95 in rats, 0.51-1 in dogs, and 0.66-0.71 in humans in vivo, suggesting minor penetration into red blood cells.
Pigmented male rats following a single oral administration:
● The drug was rapidly and well distributed into most tissues except for the central nervous system since the blood-brain barrier was crossed by a very small extent.
● Relatively higher concentrations were observed in kidneys, liver and glandular tissues especially in the renal cortex and the harderian gland, compared to other organs.
● No accumulation in tissues was observed in relevant plasma concentrations. Note that radioactivity levels in skin and eyes were comparable to those in plasma.
● Radioactivity concentrations decreased below the lower limit of quantitation in most tissues at 96 h post-dose.
Metabolism of Canagliflozin
Could be metabolized in human liver microsomes, and in mouse, rat, dog, rabbit as well as human hepatocytes.
UGT1A9 and UGT2B4 were the major metabolizing enzymes for two inactive O-glucuronide metabolites (M5 and M7).
In humans, CYP3A4-mediated (oxidative) metabolism of canagliflozin was minimal.
Overall, the parent drug represented the most abundant component, with O-glucuronidation (M5, M7) as the major metabolites in human plasma.
In non-clinical species, oxidation was the major metabolic pathway. All human metabolites were also present in at least one non-clinical species.
The major metabolites (M5, M7) had no pharmacological activity.
Excretion of Canagliflozin
Was predominantly eliminated in feces in humans and tested animals, with parent as the major component in mouse feces, M6 in rat feces and M8 in dog feces.
The reabsorption rate of biliary excreted radioactivity was calculated to be approximately 18.3% in BDC mice after intraduodenal administration.
Drug-Drug interaction
Canagliflozin did not inhibit the CYP molecular species (1A2, 2A6, 2C19, 2D6, or 2E1), but weakly inhibited CYP2B6, CYP2C8, CYP2C9, CYP3A4, UGT1A1 and UGT1A6. Meanwhile, metabolite M7 was a weak inhibitor of CYP2B6 and CYP2C8.
Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2), and metabolites M5 and M7 were not inducers of CYP1A2, 2B6 or 3A4 either.
Canagliflozin was a substrate of P-gp, BCRP and MRP2, and had weak inhibition for P-gp and MRP2, but did not inhibit BCRP.
Canagliflozin was not a substrate and inhibitor of NTCP, OAT1, OAT3, OATP1B1, OCT1 and OCT2.
In addition, metabolites M5 and M7 were not substrates of NTCP, OAT1, OAT3, OATP1B1, OCT1 and OCT2.
M5 did not inhibit these transporters, while M7 showed inhibition for NTCP, OAT3 and OATP1B1.
Update Date：2016-06-07
Single-Dose Toxicity
Single-dose oral and intraperitoneal administration of canagliflozin in mice and rats:
● Mouse MNLD: 2000 mg/kg (p.o.), and 500 mg/kg (i.p.)
● Rat MNLD: 2000 mg/kg (p.o.), 250 mg/kg (male, i.p.), and 500 mg/kg (female, i.p.)
Repeated-Dose Toxicity
Repeat-dose oral administration of canagliflozin in mice (3 months), rats (up to 6 months), and dogs (6 months):
● For mice: The NOAEL was 100 mg/kg/day (9 and 14 × MRHD for males and females, respectively), determined by the 13-week study.
● For rats: The NOAEL was 4 and 20 mg/kg/day for males and females, respectively for the 13-week study, while the NOAEL was less than 4 mg/kg/day for both males and females for the 26-week study.
● For dogs: The NOAEL was 30 and 100 mg/kg/day (10 and 19 × MRHD for males and females, respectively) for the 26-week study.
● Canagliflozin resulted in dose-dependent increase in renal tubule, pelvic and urinary tract dilatation, which were considered an adaptive response to chronic diuresis (mostly in mice and dogs).
● The key target organs of toxicity were kidneys and bone.
Safety Pharmacology
The mean photo-effect was 0.28 (>0.15), indicating that canagliflozin was phototoxic in vitro.
No cardiovascular, neurological or pulmonary side effects were found in safety pharmacological studies.
Genotoxicity
Canagliflozin was not mutagenic in the Ames assay.
Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with S9 metabolic activation.
Canagliflozin was not mutagenic or clastogenic in the in vivo micronucleus assay and in vivo comet assay in rats.
Reproductive and Developmental Toxicity
Fertility and early embryonic development: Slight alterations were found in sperm parameters and implantation in parental toxicity.
Developmental toxicity: Alterations in the pattern of ossification were noted at doses associated with maternal toxicity, but effects typically disappear as the fetus matures.
Per- and postnatal toxicity: Growth delay was revealed at doses associated with maternal toxicity.
Juvenile toxicity: Renal tubule and pelvic dilatation occurred at an increased incidence at lower doses and/or after a shorter period of dosing than that seen in adults.
Based on observations of the kidneys, appropriate statements will need to be incorporated into the label to discontinue treatment during late gestation and while nursing (lactation).
Canagliflozin crossed the placental barrier, and fetal systemic exposure was approximately the same as maternal blood exposure.
Canagliflozin and its metabolites passed into milk with the milk to plasma ratio of 1.05 to 1.55.
Carcinogenicity
Canagliflozin did not increase the incidence of tumors in mice at 10, 30, or 100 mg/kg (≤14 fold of MRHD).
Testicular Leydig cell tumors increased significantly in male rats at all doses (10, 30, or100 mg/kg), which were considered secondary to increase luteinizing hormone.
Renal tubular adenoma and carcinoma increased significantly in male and female rats at 100 mg/kg, or approximately 12 fold of MRHD.
Adrenal pheochromocytoma increased significantly in males and numerically in females at 100 mg/kg.
Carbohydrate malabsorption associated with high doses of canagliflozin was considered to be a necessary proximal event in the emergence of renal and adrenal tumors in rats.
