New Drug Approvals 2013 - Pt. V - Canagliflozin (INVOKANA™)

ATC Code: A10BX (incomplete)

Wikipedia: Canagliflozin

ChEMBL: CHEMBL2048484

On March 29th the FDA approved Canagliflozin (trade name INVOKANA™) to improve glycemic control for the treatment of diabetes type 2. Canagliflozin is to be used in combination with proper diet and exercise. Canagliflozin is a subtype 2 sodium-glucose transport protein (SGLT2, ChEMBL3884) inhibitor. Canagliflozin is a first-in-class drug with several others still in clinical trials. 

Target

SGLT2 is found in the proximal tubule of the nephron in the kidneys (as is paralog SGLT1, ChEMBL4979). SGLT2 one of the 5 known members of the sodium-glucose transporter proteins family. The transporter is responsible for 90 % of the total renal glucose reuptake (corresponding to 98 % of the uptake in the proximal convoluted tubule). The protein has a relatively low affinity for glucose compared to SGLT1 (2 mM versus 0.4 mM) but a higher capacity. Hence inhibition of this protein leads to a lowering of the glucose plasma concentration. SGLT2 is a 672 amino acid protein which can be found on Uniprot (P31639). The most similar PDB structure is the sodium/glucose costransporter from Vibrio parahaemolyticus (3DH4). 

The paralog SGLT1 (664 amino acids, 57.63% identical to SGLT2) is also found in the intestine where it is responsible for glucose uptake. Hence SGLT1 forms an important anti-target for Canagliflozin. 

Structure

Canagliflozin (CHEMBL2048484 ; Chemspider : 26333259 ;  Pubchem : 125299338 ; Unichem Identifier 1075025) is a small molecule drug with a molecular weight of 444.5 Da, an AlogP of 3.45, 5 rotatable bonds and does not violate the rule of 5.

Canonical SMILES : Cc1ccc(cc1Cc2ccc(s2)c3ccc(F)cc3)[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O

InChi: InChI=1S/C24H25FO5S/c1-13-2-3-15(24-23(29)22(28)21(27)19(12-26)30-24)10-16(13)11-18-8-9-20(31-18)14-4-6-17(25)7-5-14/h2-10,19,21-24,26-29H,11-12H2,1H3/t19-,21-,22+,23-,24+/m1/s1

Contra-indications

Canagliflozin is contra-indicated when there is a history of serious hypersensitivity reactions to Canagliflozin or in cases of severe renal impairment, ESRD, or on dialysis.

Dosage

The recommended starting dose of Canagliflozin is 100 mg once daily, taken before the first meal of the day. The dose can be increased to 300 mg once daily in patients tolerating Canagliflozin. 100 mg should be dosed once daily who have an eGFR of 60 mL/min/1.73 m² or greater and require additional glycemic control. Canagliflozin is limited to 100 mg once daily in patients who have an eGFR of 45 to less than 60 mL/min/1.73 m².Canagliflozin should be discontinued if eGFR falls below 45 mL/min/1.73 m².

Metabolism
O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.

Excretion
Following administration of a single oral [¹⁴C]canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2%  of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible. Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min. Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.

The license holder is Janssen Pharmaceuticals, Inc. and the full prescribing information can be found here.