Ertugliflozin

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H25ClO7
Molecular Weight	436.883
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCOC1=CC=C(CC2=C(Cl)C=CC(=C2)[C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)C=C1

InChI

InChIKey=MCIACXAZCBVDEE-CUUWFGFTSA-N

InChI=1S/C22H25ClO7/c1-2-28-16-6-3-13(4-7-16)9-14-10-15(5-8-17(14)23)22-20(27)18(25)19(26)21(11-24,30-22)12-29-22/h3-8,10,18-20,24-27H,2,9,11-12H2,1H3/t18-,19-,20+,21-,22-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21449606 | https://www.ncbi.nlm.nih.gov/pubmed/25754396 | http://www.pfizer.com/news/press-release/press-release-detail/merck_and_pfizer_announce_u_s_fda_and_ema_filing_acceptances_of_three_marketing_applications_for_ertugliflozin_containing_medicines_for_adults_with_type_2_diabetes

Ertugliflozin (PF-04971729) is a potent and selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. SGLT2 has become an important therapeutic target and several SGLT2-selective inhibitors are either approved or in clinical development for the management of blood glucose in patients with type 2 diabetes. Ertugliflozin demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It was announced that FDA and EMA filing acceptances of three marketing applications for ertugliflozin-containing medicines for adults with type 2 diabetes.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Sodium/glucose cotransporter 2 25 Target ID: CHEMBL3884 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21449606	Inhibitor 8297		0.877 nM [IC50]
Sodium/glucose cotransporter 1 7 Target ID: CHEMBL4979 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21449606	Inhibitor 8297		1960.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: https://clinicaltrials.gov/ct2/show/NCT01986881	Primary		Phase III 656	ERTUGLIFLOZIN Approved Use Unknown
type 2 diabetes mellitus 5 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209803s000lbl.pdf	Primary		Approved 8429	STEGLATRO Approved Use STEGLATRO™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Launch Date 2017

C_max

Value	Dose	Co-administered	Analyte	Population
81.3 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209803s000lbl.pdf	5 mg 1 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ERTUGLIFLOZIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
398 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209803s000lbl.pdf	5 mg 1 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ERTUGLIFLOZIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
16.6 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209803s000lbl.pdf	5 mg 1 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ERTUGLIFLOZIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
6.4% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209803s000lbl.pdf	5 mg 1 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ERTUGLIFLOZIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p. 97	unhealthy, > 65 years n = 1693 Health Status: unhealthy Age Group: > 65 years Population Size: 1693 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p. 97	Disc. AE: Hyperglycaemia, Glomerular filtration rate decreased... AEs leading to discontinuation/dose reduction: Hyperglycaemia (0.5%) Glomerular filtration rate decreased (0.4%) Balanoposthitis (0.1%) Urinary tract infection (0.2%) Vulvovaginal mycotic infection (0.1%) Acute kidney injury (0.1%) Pollakiuria (0.2%) Vulvovaginal pruritus (0.1%) Vulvovaginal candidiasis (0.2%) Diarrhoea (0.1%) Nausea (0.1%) Weight decreased (0.1%) Acute myocardial infarction (0.1%) Blood creatinine increased (0.1%) Dysuria (0.1%) Genital candidiasis (0.1%) Hypoglycaemia (0.1%) Insomnia (0.1%) Non-cardiac chest pain (0.1%) Polyuria (0.1%) Pruritus genital (0.1%) Rash (0.1%) Incontinence urinary (0.1%) Abdominal pain (0.1%) Alopecia (0.1%) Arthralgia (0.1%) Asthma (0.1%) Benign ovarian tumor (0.1%) Cellulite (0.1%) Cholelithiasis (0.1%) Colon cancer (0.1%) Dermatitis allergic (0.1%) Diabetic ketoacidosis (0.1%) Dry mouth (0.1%) Dysphonia (0.1%) Endometrial adenocarcinoma (0.1%) Fatigue (0.1%) Haematuria (0.1%) Headache (0.1%) Jaundice cholestatic (0.1%) Liver disorder (0.1%) Malaise (0.1%) Metabolic acidosis (0.1%) Mood swings (0.1%) Nightmare (0.1%) Pancreatic neoplasm (0.1%) Penile pain (0.1%) Peripheral ischaemia (0.1%) Peripheral swelling (0.1%) Plasma cell myeloma (0.1%) Prurigo (0.1%) Rash maculo-papular (0.1%) Septic shock (0.1%) Vision blurred (0.1%) Vulvovaginitis (0.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p. 97
5 mg 1 times / day steady, oral (starting) Recommended Dose: 5 mg, 1 times / day Route: oral Route: steady Dose: 5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p. 97	unhealthy, > 65 years n = 1716 Health Status: unhealthy Age Group: > 65 years Population Size: 1716 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p. 97	Disc. AE: Hyperglycaemia, Glomerular filtration rate decreased... AEs leading to discontinuation/dose reduction: Hyperglycaemia (0.3%) Glomerular filtration rate decreased (0.1%) Balanoposthitis (0.3%) Urinary tract infection (0.1%) Vulvovaginal mycotic infection (0.2%) Acute kidney injury (0.1%) Pollakiuria (0.1%) Vulvovaginal pruritus (0.1%) Vulvovaginal candidiasis (0.1%) Diarrhoea (0.1%) Dizziness (0.2%) Nausea (0.1%) Weight decreased (0.1%) Abdominal pain upper (0.1%) Acute myocardial infarction (0.1%) Blood creatinine increased (0.1%) Dysuria (0.1%) Genital candidiasis (0.1%) Hypoglycaemia (0.1%) Insomnia (0.1%) Non-cardiac chest pain (0.1%) Polyuria (0.1%) Pruritus genital (0.1%) Rash (0.1%) Rheumatoid arthritis (0.1%) Adenocarcinoma gastric (0.1%) Alanine aminotransferase increased (0.1%) Aspartate aminotransferase increased (0.1%) Asthenia (0.1%) Blood glucose increased (0.1%) Breast cancer (0.1%) Cerebral infarction (0.1%) Cerebrovascular accident (0.1%) Coronary artery disease (0.1%) Diabetic foot (0.1%) Diabetic neuropathy (0.1%) Dyslipidaemia (0.1%) Face injury (0.1%) Facial paralysis (0.1%) Fungal skin infection (0.1%) Genital infection (0.1%) Head discomfort (0.1%) Hepatocellular injury (0.1%) Humerus fracture (0.1%) Hunger (0.1%) Hyperchlorhydria (0.1%) Musculoskeletal pain (0.1%) Myocardial infarction (0.1%) Nephropathy (0.1%) Obesity (0.1%) Oral candidiasis (0.1%) Osteomyelitis acute (0.1%) Pain in extremity (0.1%) Acute pancreatitis (0.1%) Pyelonephritis (0.1%) Pyelonephritis acute (0.1%) Thirst (0.1%) Urinary retention (0.1%) Urogenital infection fungal (0.1%) Vaginal infection (0.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p. 97
15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p.84	unhealthy, adult n = 1693 Health Status: unhealthy Age Group: adult Population Size: 1693 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p.84	Other AEs: Acute myocardial infarction, Haemorrhagic stroke... Other AEs: Acute myocardial infarction (grade 5, 0.18%) Haemorrhagic stroke (grade 5, 0.06%) Ischaemic stroke (grade 5, 0.06%) Septic shock (grade 5, 0.06%) Plasma cell myeloma (grade 5, 0.06%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p.84
5 mg 1 times / day steady, oral (starting) Recommended Dose: 5 mg, 1 times / day Route: oral Route: steady Dose: 5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p.84	unhealthy, adult n = 1716 Health Status: unhealthy Age Group: adult Population Size: 1716 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p.84	Other AEs: Acute myocardial infarction, Cardiac death... Other AEs: Acute myocardial infarction (grade 5, 0.06%) Cardiac death (grade 5, 0.17%) Multiple organ dysfunction syndrome (grade 5, 0.06%) Pneumonia (grade 5, 0.06%) Chronic obstructive pulmonary disease (grade 5, 0.06%) Depression (grade 5, 0.06%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000MedR.pdf Page: p.84
100 mg 1 times / day steady, oral Highest studied dose Dose: 100 mg, 1 times / day Route: oral Route: steady Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32337660	healthy Health Status: healthy Sources: https://pubmed.ncbi.nlm.nih.gov/32337660	Sources: https://pubmed.ncbi.nlm.nih.gov/32337660
300 mg single, oral Highest studied dose Dose: 300 mg Route: oral Route: single Dose: 300 mg Sources: https://pubmed.ncbi.nlm.nih.gov/32337660	healthy Health Status: healthy Sources: https://pubmed.ncbi.nlm.nih.gov/32337660	Sources: https://pubmed.ncbi.nlm.nih.gov/32337660

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	substrate 1037 inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A5 73 CYP2C8 911 CYP1A2 1524 CYP2C19 1478 CYP2B6 810 Nav1.5 97 UGT1A1 204 UGT1A4 77 UGT1A6 108 UGT1A9 116 UGT2B7 146 P-gp 1461 BCRP 699 OCT1 512 OCT2 647 OAT1 599 OAT3 642 OATP1B1 788 OATP1B3 706	UGT1A1 418 UGT1A4 347 UGT1A6 307 UGT1A9 380 UGT2B7 389 CYP1A2 1054 CYP2B6 664 CYP3A5 395 CYP2C8 693 CYP2C19 991 P-gp 1537 BCRP 561 OAT1 326 OAT3 339 OCT1 327 OCT2 355 OATP1B1 406 OATP1B3 350	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=42 Page: (NDA209803) 11, 28, 29, 206, 207, 210, (NDA209805) 44, (NDA209806) 44, (ClinPharm) 41-42, 91-92	no [IC50 917 uM]	no (co-administration study) Comment: Ki = 917 mcM; Not meaningfully inhibit at clinically relevant concentrations; Coadministration of ertugliflozin (15 mg SD) decreased metformin (OCT2 substrate, 1000 mg SD) Cmax by 6% and increased AUCinf by 0.94%. There are no meaningful difference in the PK of metformin when it is administered with ertugliflozin, as compared to single dose of metformin alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=42 Page: (NDA209803) 11, 28, 29, 206, 207, 210, (NDA209805) 44, (NDA209806) 44, (ClinPharm) 41-42, 91-92
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186 Page: (IND106447) 21, (NDA209803) 10, 27, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no [IC50 >30 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186 Page: (IND106447) 21, (NDA209803) 10, 27, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no [IC50 >30 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186 Page: (IND106447) 21, (NDA209803) 10, 27, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no [IC50 >30 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186 Page: (IND106447) 21, (NDA209803) 10, 27, 206, 207, (NDA209805) 11, 44, (NDA209806) 11, 44	no [IC50 >30 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186 Page: (IND106447) 21, (NDA209803) 10, 27, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no [IC50 >30 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=44 Page: (IND106447) 21, (NDA209803) 10, 27, 29, 206, 207, (NDA209805) 44, (NDA209806) 44, (ClinPharm) 43-44, 94-95	no [IC50 >30 uM]	no (co-administration study) Comment: Ki > 15 mcM; Not a reversible or time-dependent inhibitor (humna liver microsomes), IC50 value (>30 mcM) is at least 50-fold higher than clinical ertugliflozin Cmax concentrations (0.6 mcM).; Coadministration of ertugliflozin (15 mg SD) decreased glimepiride (1 mg SD) Cmax by 2.61% and increased AUCinf by 9.80%. There are no meaningful difference in the PK of glimepiride when it is administered with ertugliflozin, as compared to single dose of glimepiride alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=44 Page: (IND106447) 21, (NDA209803) 10, 27, 29, 206, 207, (NDA209805) 44, (NDA209806) 44, (ClinPharm) 43-44, 94-95
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=41, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=46 Page: (IND106447) 21, (NDA209803) 10, 27, 29, 206, 207 (NDA209805) 11, 44, (NDA209806) 11, 44, (ClinPharm) 39-40, 89-90, 45-46, 96-98	no [IC50 >30 uM]	no (co-administration study) Comment: Ki > 15 mcM; Not a reversible or time-dependent inhibitor (humna liver microsomes), IC50 value (>30 mcM) is at least 50-fold higher than clinical ertugliflozin Cmax concentrations (0.6 mcM)., Coadministration of ertugliflozin (15 mg SD) increased sitagliptin (CYP3A4 substarte, 100 mg SD) Cmax by 1.68% and AUCinf by 1.67%. There are no meaningful difference in the PK of sitagliptin when it is administered with ertugliflozin, as compared to single dose of sitagliptin alone., Coadministration of ertugliflozin (15 mg SD) increased simvastatin (CYP3A substrate, 40 mg SD) Cmax by 19.05% and AUCinf by 23.83%. There are no meaningful difference in the PK of glimepiride when it is administered with ertugliflozin, as compared to single dose of simvastatin alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=186, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=41, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=46 Page: (IND106447) 21, (NDA209803) 10, 27, 29, 206, 207 (NDA209805) 11, 44, (NDA209806) 11, 44, (ClinPharm) 39-40, 89-90, 45-46, 96-98
CYP3A5 130	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=46 Page: (IND106447) 21, (NDA209803) 29, (ClinPharm) 45-46, 96-98	no [Ki >15 uM]	no (co-administration study) Comment: Ki > 15 mcM; Not a reversible or time-dependent inhibitor (humna liver microsomes); Coadministration of ertugliflozin (15 mg SD) increased simvastatin (CYP3A substrate, 40 mg SD) Cmax by 19.05% and AUCinf by 23.83%. There are no meaningful difference in the PK of glimepiride when it is administered with ertugliflozin, as compared to single dose of simvastatin alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=46 Page: (IND106447) 21, (NDA209803) 29, (ClinPharm) 45-46, 96-98
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 11, 28, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no [Ki >250 uM]
UGT1A6 141	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 10, 28, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no [Ki >50 uM]
UGT1A9 121	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 10, 28, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no [Ki >50 uM]
UGT2B7 157	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 10, 28, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no [Ki >50 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (IND122329) 15, (IND106447) 21, (NDA209803) 27, 29, 206, 207, 210(NDA209803) 10, (NDA209805) 44, (NDA209806) 44	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45 Page: (NDA209803) 10, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (IND106447) 21, (NDA209803) 27, 29, 206, 207, 210, (NDA209803) 10, (NDA209805) 44, (NDA209806) 44	no
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (IND106447) 21, (NDA209803) 11, 28, 29, 207, 210	weak [IC50 140.7 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 11, 28, 29, 206, 207, 210, (NDA209805) 44, (NDA209806) 44	weak [IC50 176 uM]
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (IND106447) 21, (NDA209803) 11, 28, 29, 207, 210	weak [IC50 35.4 uM]
UGT1A1 254	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 10, 28, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	weak [IC50 39 uM]
UGT1A4 80	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 10, 28, 29, 206, 207, (NDA209805) 44, (NDA209806) 44	weak [IC50 45 uM]
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 28, 29, 210	weak [IC50 53 uM]
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (IND106447) 21, (NDA209803) 11, 28, 29, 206, 207, 210, (NDA209805) 44, (NDA209806) 44	weak [IC50 70 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=187 Page: (NDA209803) 28, 29, 210	weak [Inhibition 100 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
UGT1A9 380	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12 Page: (NDA209803) 10, 29, (NDA209805) 11, 43, (NDA209806) 11, 43, (NDA ClinPharm) 47-48, 99-100	major	yes (co-administration study) Comment: Coadministration of ertugliflozin (15 mg SD) with multiple doses of rifampicin (an inducer of UGT and CYP emzymes, 600 mg QD) decreased ertugliflozin Cmax by 15.38% and AUCinf by 38.84%. Mean terminal t1/2 was 12.3 hr for ertugliflozin administered alone compared to 9.2 hr for ertugliflozin coadministered with rifampicin. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12 Page: (NDA209803) 10, 29, (NDA209805) 11, 43, (NDA209806) 11, 43, (NDA ClinPharm) 47-48, 99-100
UGT2B7 389	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12 Page: (NDA209803) 10, 29, (NDA209805) 11, 43, (NDA209806) 11, 43	major	yes (co-administration study) Comment: Coadministration of ertugliflozin (15 mg SD) with multiple doses of rifampicin (an inducer of UGT and CYP emzymes, 600 mg QD) decreased ertugliflozin Cmax by 15.38% and AUCinf by 38.84%. Mean terminal t1/2 was 12.3 hr for ertugliflozin administered alone compared to 9.2 hr for ertugliflozin coadministered with rifampicin. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12 Page: (NDA209803) 10, 29, (NDA209805) 11, 43, (NDA209806) 11, 43
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12 Page: (NDA209803) 29, (NDA209805) 11, (NDA209806) 11	minor
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=40, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=45 Page: (NDA209803) 29, (NDA209805) 11, (NDA209806) 11, (ClinPharm) 39, 89-90, 44-45, 96-98	minor	yes (co-administration study) Comment: Coadministration of ertugliflozin (15 mg SD) with multiple doses of rifampicin (an inducer of UGT and CYP emzymes, 600 mg QD) decreased ertugliflozin Cmax by 15.38% and AUCinf by 38.84%. Mean terminal t1/2 was 12.3 hr for ertugliflozin administered alone compared to 9.2 hr for ertugliflozin coadministered with rifampicin., Coadministration of sitagliptin (metabolized by CYP3A4, 100 mg SD) decreased Cmax of ertugliflozin (15 mg SD) by 1.82% and increased AUCinf by 2.27%. There are no meaningful difference in the PK of ertugliflozin when it is administered with sitagliptin, as compared to single dose of ertugliflozin alone., Coadministration of simvastatin (CYP3A substrate, 40 mg SD) increased Cmax of ertugliflozin (15 mg SD) by 5.16% and AUCinf by 2.40%. There are no meaningful difference in the PK of ertugliflozin when it is administered with simvastatin, as compared to single dose of ertugliflozin alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=40, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=45 Page: (NDA209803) 29, (NDA209805) 11, (NDA209806) 11, (ClinPharm) 39, 89-90, 44-45, 96-98
CYP3A5 395	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=45 Page: (NDA209803) 29, (NDA209805) 11, (NDA209806) 11, (ClinPharm) 44-45, 96-98	minor	yes (co-administration study) Comment: Coadministration of ertugliflozin (15 mg SD) with multiple doses of rifampicin (an inducer of UGT and CYP emzymes, 600 mg QD) decreased ertugliflozin Cmax by 15.38% and AUCinf by 38.84%. Mean terminal t1/2 was 12.3 hr for ertugliflozin administered alone compared to 9.2 hr for ertugliflozin coadministered with rifampicin., Coadministration of simvastatin (CYP3A substrate, 40 mg SD) increased Cmax of ertugliflozin (15 mg SD) by 5.16% and AUCinf by 2.40%. There are no meaningful difference in the PK of ertugliflozin when it is administered with simvastatin, as compared to single dose of ertugliflozin alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=12, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=45 Page: (NDA209803) 29, (NDA209805) 11, (NDA209806) 11, (ClinPharm) 44-45, 96-98
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (NDA209803) 29	no
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (NDA209803) 29	no
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (NDA209803) 29	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (NDA209803) 29	no
OAT1 326	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45 Page: (IND106447) 21, (NDA209803) 10, 29, 206, 207, 210 (NDA209805) 44, (NDA209806) 44	no
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45 Page: (IND106447) 21, (NDA209803) 11, 29, 206, 207, 210, (NDA209805) 44, (NDA209806) 44	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45 Page: (NDA209803) 11, 29, 206, 207, 210, (NDA209805) 44, (NDA209806) 44	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45 Page: (NDA209803) 11, 29, 206, 207, 210, (NDA209805) 44, (NDA209806) 44	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45 Page: (NDA209803) 11, 29, 206, 207,210, (NDA209805) 44, (NDA209806) 44	no
UGT1A1 418	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (NDA209803) 29	no
UGT1A4 347	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (NDA209803) 29	no
UGT1A6 307	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=188 Page: (NDA209803) 29	no
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=43 Page: (NDA209803) 29, (ClinPharm) 42-43, 94-95	no	no (co-administration study) Comment: Coadministration of glimepiride (1 mg SD) decreased Cmax of ertugliflozin (15 mg SD) by 1.80% and increased AUCinf by 2.11%. There are no meaningful difference in the PK of ertugliflozin when it is administered with glimepiride, as compared to single dose of ertugliflozin alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=43 Page: (NDA209803) 29, (ClinPharm) 42-43, 94-95
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=41 Page: (IND106447) 21, (NDA209803) 11, 29, 206, 207,210, (NDA209805) 44, (NDA209806) 44, (ClinPharm) 40-41, 91-92	no	no (co-administration study) Comment: Coadministration of metformin (OCT2 substrate, 1000 mg SD) decreased Cmax of ertugliflozin (15 mg SD) by 2.86% and increased AUCinf by 0.34%. There are no meaningful difference in the PK of ertugliflozin when it is administered with metformin, as compared to single dose of ertugliflozin alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000ClinPharmR.pdf#page=41 Page: (IND106447) 21, (NDA209803) 11, 29, 206, 207,210, (NDA209805) 44, (NDA209806) 44, (ClinPharm) 40-41, 91-92
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=45 Page: (NDA209803) 10, 29, 206, 207,120, (NDA209803) 10, (NDA209805) 44, (NDA209806) 44	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=15 Page: (IND106447) 27, (NDA209803) 29, 32, 206, 207, 210, (NDA209805) 14, 44, (NDA209806) 14, 44	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
Nav1.5 100	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=13 Page: (IND106447) 4, 21, 22-23, (NDA209803) 22, (NDA209805) 12, (NDA209806) 12
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000PharmR.pdf#page=13 Page: (IND106447) 4, 21, (NDA209803) 22, (NDA209805) 12, (NDA209806) 12

Sourcing

Vendor/Aggregator	ID	URL
AA Blocks	AA003A9D	https://www.aablocks.com/goods/Goods/detail?id=AA003A9D
AK Scientific, Inc. (AKSCI)	Y0303	http://www.aksci.com/item_detail.php?cat=Y0303
Aaron Chemicals	AR003B15	http://www.aaronchem.com/1210344-57-2
AbMole Bioscience	M6272	http://www.abmole.com/products/pf04971729.html
Achemtek	0102-013970	http://www.achemtek.com/1210344-57-2
Acorn PharmaTech	ACN-037560	http://www.acornpharmatech.com/
Active Biopharma	ABP000359	http://www.activebiopharma.com/1210344-57-2
Adooq BioScience	A11102	https://www.adooq.com/pf-04971729.html
Ambinter	Amb22170013	http://www.ambinter.com/reference/22170013
Ark Pharma Scientific Limited	A-0297	http://www.arkpharmtech.com/product/32248.html
Aurum Pharmatech LLC	W-5850	http://www.Aurumpharmatech.com/Product/ProductDetails/W_5850
BLD Pharm	BD304675	http://www.bldpharm.com/products/1210344-57-2.html
BioCrick	BCC1852	http://www.biocrick.com/PF-04971729-BCC1852.html
BioSynth	J-504029	https://www.biosynth.com/en/products/all-products/products/J-504029.html
Boerchem	BC638832	http://www.boerchem.com/?product_42967.html
CSNpharm	CSN15831	https://www.csnpharm.com/products/pf-04971729.html
Chem Scene	CS-0976	http://www.chemscene.com/1210344-57-2.html
Chemspace	CSSB00020641842	https://chem-space.com/CSSB00020641842
Excenen	EX-A407	http://www.excenen.com/searchresultlist.php?id=1210344-57-2
Lancrix Chemicals	634076	http://www.lancrix.com/product/detail-14-1313.htm
Matrix Scientific	123405	https://www.matrixscientific.com/123405.html
MedChem Express	HY-15461	https://www.medchemexpress.com/PF-04971729.html
MuseChem	I000787	https://www.musechem.com/product/I000787.html
Renno Tech	RL00877	http://www.rennotech.com/product_show.asp?id=416
Selleck Chemicals	S5413	http://www.selleckchem.com/products/ertugliflozin.html
Smolecule	S527392	http://www.smolecule.com/products/s527392
Synblock Inc	SB11082	http://www.synblock.com/product/1210344-57-2.html
THE BioTek	bt-267650	https://www.thebiotek.com/product/inhibitors/bt-267650
TubePharm	Tube108	http://www.tubepharm.com/product/1210344-57-2-en.html
abcr GmbH	AB442952	http://www.abcr.com/shop/en/AB442952
eNovation Chemicals	D501870	http://www.enovationchem.com/productDetails.asp?productID=D501870
eNovation Chemicals	D572101	https://www.enovationchem.com/ProductDetails.asp?ProductID=D572101
eNovation Chemicals	Y0974040	https://www.enovationchem.com/ProductDetails.asp?ProductID=Y0974040

PubMed

Title	Date	PubMed
Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors.	2011 Apr 28	21449606

Patents

Sample Use Guides

In Vivo Use Guide

Once-daily ertugliflozin (1, 5, 10 or 25 mg) for the 12-week treatment period.

Route of Administration: Oral

In Vitro Use Guide

Ertugliflozin (PF-04971729), at a concentration range of 1.4 to 1000 μM, was evaluated as an inhibitor of the hOCT2 transporter. The calculated IC50 for inhibition of hOCT2-mediated uptake of [14C]metformin by PF-04971729 was 917 uM. Under these experimental conditions, the positive control quinidine (1 mM) inhibited >80% [14C]metformin uptake mediated by hOCT2.

Name

Type

Language

Ertugliflozin

Official Name

English

1,6-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-5-C-(hydroxymethyl)-β-L-idopyranose

Systematic Name

English

PF04971729

Code

English

(1S,2S,3S,4R,5S)-5-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

Systematic Name

English

ERTUGLIFLOZIN [MI]

Common Name

English

β-L-Idopyranose, 1,6-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-5-C-(hydroxymethyl)-

Systematic Name

English

PF-04971729

Code

English

ERTUGLIFLOZIN [ORANGE BOOK]

Common Name

English

ertugliflozin [INN]

Common Name

English

Ertugliflozin [WHO-DD]

Common Name

English

ERTUGLIFLOZIN [USAN]

Common Name

English

PF-04971729-00

Code

English

MK-8835

Code

English

Classification Tree Code System Code

WHO-ATC

A10BD24