Dapagliflozin Propanediol Monohydrate
Dapagliflozin propanediol monohydrate was first approved by European Medicine Agency (EMA) on November 12, 2012, then approved by the U.S. Food and Drug Administration (FDA) on January 8, 2014, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on March 24, 2014. It was co-developed and co-marketed as Forxiga® by Bristol-Myers Squibb and AstraZeneca in EU.
Dapagliflozin propanediol monohydrate is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Forxiga® is available as tablet for oral use, containing 5 mg or 10 mg of free Dapagliflozin. The recommended starting dose is 5 mg once daily in the morning.
Update Date：2016-03-21
- Drug Name：
- Dapagliflozin Propanediol Monohydrate
- Research Code：
- BMS-512148-05
- Trade Name：
- Forxiga® / Farxiga®
- MOA：
- Sodium-glucose cotransporter 2 (SGLT2) inhibitor
- Indication：
- Type 2 diabetes
- Status：
- Approved
- Company：
- Bristol-Myers Squibb (Originator) , AstraZeneca
- Sales：
-
$518.7 Million (Y2015);
$235.8 Million (Y2014);
$33 Million (Y2013); - ATC Code：
- A10BX09
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-01-08 | Marketing approval | Farxiga | Type 2 diabetes | Tablet | 5 mg/10 mg | AstraZeneca |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2012-11-12 | Marketing approval | Forxiga | Type 2 diabetes | Tablet, Film coated | Eq. 5 mg/10 mg Dapagliflozin | Bristol-Myers Squibb, AstraZeneca |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-03-24 | Marketing approval | Forxiga | Type 2 diabetes | Tablet, Film coated | 5 mg/10 mg | Bristol-Myers Squibb, AstraZeneca, Ono |
Update Date：2015-09-16
|
Molecular Weight | 502.98 | ||||||||||||
| Formula | C21H25ClO6•C3H8O2•H2O | |||||||||||||
| CAS No. |
461432-26-8 (Dapagliflozin); 960404-48-2 (Dapagliflozin Propanediol Monohydrate); |
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| Chemical Name | (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,(2S)-propane-1,2-diol(1:1) monohydrate | |||||||||||||
| Dapagliflozin （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-12-03
Update Date：2016-05-30
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1. WO2010022313 / US8283454B2.
1. WO2013068850.
Update Date：2016-06-13
Mechanism of Action
● Usually 90% of filtered glucose is reabsorbed by SGLT2 (sodium-glucose linked transporter 2) in the kidney.
● Dapagliflozin selectively inhibits SGLT2 leading to excretion of excess glucose in the urine by reducing glucose reabsorption.
● Inhibition of human SGLT2: Ki = 0.55 nM; EC50=1 nM.
● About 1400 times more selective for human SGLT2 vs SGLT1.
● Dapagliflozin does not inhibit another type of glucose transporter GLUT1 or GLUT4.
In Vivo Efficacy
● Plasma glucose lower effective dose of dapagliflozin:
v Non-diabetic SD rats (single dose): 1.0 and 10 mg/kg.
v STZ-induced diabetic SD rats (single dose): 0.03 and 0.1 mg/kg.
v ZDF diabetic rats (single dose): 0.1 and 1.0 mg/kg.
v ZDF diabetic rats (repeated dose): ≥ 0.1 mg/kg.
Update Date：2016-06-14
Absorption
● Bioavailability: 84% (rat), 83% (dog), 25% (Monkey), 77% (human).
● A longer half-life time in humans (13 hrs) than in the rat, monkey or dog (3-7 hrs), suggestive of different rates of renal elimination.
● The volume of distribution in human was 118 L, indicating extravascular tissue distribution.
● Moderate absorption permeability with Papp A-B >15×10-6 cm/s in Caco-2 model.
Distribution
● Plasma protein binding was high (91-95%) in humans and in all nonclinical species.
● Rapid distribution to most rat tissues with low amount finding in the brain and bone.
Metabolism
● In vitro low (10%) oxidative metabolism underwent by numerous human cytochrome P450 enzymes.
● Dapagliflozin 3-O-glucuronide was the major human metabolite formed in the kidney and also the liver.
● UGT1A9 was the major human UDP-glucuronosyltransferase, which was responsible for the formation of dapagliflozin 3-O-glucuronide and was predominantly found in the kidney.
● No unique dapagliflozin human metabolites were identified.
Excretion
● Excretion was predominately via metabolism to the dapagliflozin 3-O-glucuronide followed by excretion in the urine. The parent was also found to a much lower extent in the urine, feces and bile.
● Dapagliflozin was also found to be excreted in the milk of lactating rats.
Drug-Drug Interaction
● Minimal inhibition on multiple cytochrome P450 enzymes with an IC50 at > 40 μM.
● Not to be an in vitro inducer of CYP3A4, CYP1A2 and CYP2B6.
● A weak substrate of P-gp, but was unlikely to be a P-gp inhibitor.
● Dapagliflozin was not a substrate of renal and hepatic uptake transporters OCT2, OAT1 and OATP1B1, OATP1B3, but was substrate of OAT3.
● Dapagliflozin did not inhibit OAT1 or OCT2 and was weak inhibitor of OAT3 and OATP.
Update Date：2016-06-14
Single Dose Toxicity
● Mice MTD: 1500 mg/kg, based on hunched posture and reduced activity at ≥1500 mg/kg.
● Rats MTD: 375 mg/kg, based on treatment-related deaths at ≥750 mg/kg.
● Dogs MTD: ≥1000 mg/kg, based on no severe adverse effects observed during the treatment but emesis was found in all treatment groups.
Repeated Dose Toxicity
● For mice, after 104 weeks of daily oral administration of dapagliflozin, NOAEL was 40 mg/kg/day and 20 mg/kg/day for male and female group respectively, which was 72 fold and 105 fold of MRHD based on human 10 mg exposure.
● For rats, after 13 weeks and 26 weeks of daily oral administration of dapagliflozin, NOAELs were 50 mg/kg/day and 25 mg/kg/day respectively, which were 483~941 fold of MRHD and 346~675 fold of MRHD based on human 10 mg exposure.
● For dogs, after 52 weeks of daily oral administration of dapagliflozin, NOAEL was 20 mg/kg/day, which was 561 fold of MRHD for male while 619 fold of MRHD for female based on human 10 mg exposure.
● Dapagliflozin had an osmotic diuretic effect in all species and at all doses tested and induced an increase in food and water consumption.
Safety Pharmacology
● Dapagliflozin weakly inhibited hERG potassium current by 3.7% and 15% at 10 and 30 μM and had no effect on Purkinje fiber action potential at 2, 10 and 30 μM.
● No Neurological or Pulmonary side effects found in safety pharmacological studies.
Genotoxicity
● Significantly increased frequency of chromosome structural aberration at ≥ 200 μg/mL with S9 activation, but with great dose margin based on human 10 mg exposure was 0.465 μg·hr/mL.
Reproductive and Developmental Toxicity
● Male rats fertility toxicity : NOAEL was 15 mg/kg/day, which was 160 fold of MRHD.
● Female rats fertility toxicity: NOAEL was 15 mg/kg/day, which was 188 fold of MRHD.
● Rats fetal embryonic developmental toxicity: NOAEL was 3 mg/kg/day, which was 39 fold of MRHD.
● Postnatal developmental toxicity: NOAEL was determined as 15 mg/kg/day, which was 249 fold of MRHD.
● Dapagliflozin distributed quickly to tissues including placenta and fetus in pregnant rat, blood placenta transfer ratio was fetal/maternal = 64%.
● Milk excretion of dapagliflozin was also found in lactating rats, and excretion ration was: fetal/maternal=75%.
Carcinogenicity
● No significant malignant or benign neoplasm was found in 2-year standard carcinogenicity study of both mice and rats.
