(3R)-3-amino-1-[9- (trifluoromethyl)- 1,4,7,8- tetrazabicyclo[4.3.0] nona-6,8-dien-4-yl]-
4-(2,4,5- trifluorophenyl) butan-1-one, MK-0431Sitagliptin
From Ganfyd
rINN: Sitagliptin
Other Names
Sitagliptin phosphate, Januvia®
Pharmacological Information
Pharmacology Images
Web information on Sitagliptin
Mechanism of Action
Dipeptidyl peptidase-4-inhibitor
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature
Please read pharmacological data limitations
Other Wikis
Medpedia on Sitagliptin (Less technical, good quality control)
Wikipedia on Sitagliptin (Less technical, ? quality control)
Contents |
Introduction
Known to reduce fasting and postprandial blood glucose in human type 2 diabetics, suppressing plasma glucagon and increasing the insulin to glucose ratio.[1]
Clinical Use
Type 2 diabetics
Indications
- Not first line although recently licensed in EU for monotherapy
- Improve glycaemic control in combination with:
Administration
Oral 100mg od
Clinical Issues
- First of class
Contra-indications
Cautions and Interactions
Long term effects would not be unexpected as DPP-4 and similar serine peptidases are widely expressed and for example is involved in lymphocyte function. Indeed the relative specifity and selectively of the drug might turn out to be important[2].
Side effects
Special advice
Pharmacology
Dipeptidyl peptidase-4-inhibitor
Development and Marketing
The development and marketing timeframe of sitagliptin (MK-0431) illustrate the timescales implicate in modern drug development. see pdf link for details of the complex process. Inhouse Merck had to develop the theory of DPP8 and DPP9 inhibition toxicity[4] (which is now well characterised in multiple animal models) and rely on the serendipity of having an unexpected candidate compound in its own in house screening panel. The idea for this timeline came from an analysis by Dr. D Kao directed at the marketing[5]. The first full peer reviewed studies where patients had been on other agents were published after licensing although these results had been reported in abstract well before then.
- 1997 Actions of glucagon-like peptide 1 (GLP-1) in diabetics reported[6].
- 1998 First report in mammal of dipeptidyl peptidase-IV inhibitor with hypoglycaemic effect[7]
- 1999 DPP4 inhbitor programme commenced at Merck [8]
- 2000 P32/98 (isoleucyl thiazolidide) brought in by Merck for development which was discontinued early in 2001 due to animal toxicity after first phase 2 trials
- Jan 2002 MK-0431 ([(2R)-4-oxo-4-(3-[trifluoromethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7[8H]-yl)-1-(2,4,5-trifluorophenyl)butan-2-amine]) becomes lead candidate in Merck development programme
- 16 January 2003 first relevant US patent filing
- Jan 2005 First literature report on drug's properties in diabetes[9]
- 7 April 2005 Januvia trademark filing
- 2005 First phase 3 reports [10]
- Dec 2005 Single dose phase 2 studies reported[11]
- Jan 2006 Multi-dose phase 2 studies reported[12]
- June 2006 Sitagliptin gives same glucose-lowering effect as glipizide - American Diabetes Association Meeting
- Aug 2006 Phase 2 studies reported in normal obese patients[13]
- 17 Oct 2006 FDA approval of Januvia®
- Launch + 90 minutes - Product website functional
- Launch + 48 hours Commence marketing campaign
- Messages:
- New class of drug
- Versatility as both single and add-on treatment
- Partnership with the American Diabetic Association to produce educational materials and patient guidebooks
- Train diabetes educators with goals:
- Prompting undiagnosed patients to seek testing
- Identify cases in which treatment goals are not being met.
- Education forums commenced
- First doctor contacts by sales representatives
- Media broadcasts via web and video link to healthcare providers
- Messages:
- Launch + 8 days
- Reached 70% targeted US doctors
- US Retail pharmacies have stock
- Launch + 14 days
- Completion of discussions with all US managed care organisations (covering 73% of insured US population)
- Launch + 30 days
- 14% of all new scripts for type 2 diabetes drugs by primary care prescribers
- 20% of all new scripts for type 2 diabetes drugs by endocrinologists
- Oct 2006 Phase 3 trial reported sitagliptin added to ongoing pioglitazone therapy[14]
- Dec 2006 Phase 3 trial reported sitagliptin added to ongoing metformin therapy [15]
- Dec 2006 Tradename Janumet® announced for MK-0431A, the combination of sitagliptin and metformin
- 26 Mar 2007 EMEA approval
- Sept 2007 Phase 3 trial reported in patients inadequately controlled on glimepiride alone or on glimepiride and metformin[16]
- 2007 Three million scripts and second most prescribed branded oral hypoglycaemic
- 5 Feb 2008 Full US patent granted
- 2008 first quarter sales US$272 million
- July 2008 EMEA approval Janumet, more than five million prescriptions for sitagliptin worldwide since launch
- Oct 2008 NICE issues draft guideline for newer agents in diabetes
References
- ↑ Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. The Journal of clinical endocrinology and metabolism. 2004;89:2078-84.
- ↑ Lankas GR, Leiting B, Roy RS, Eiermann GJ, Beconi MG, Biftu T, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005;54:2988-94.
- ↑ FDA Information for Healthcare Professionals - Acute pancreatitis and sitagliptin (marketed as Januvia and Janumet)
- ↑ Lankas GR, Leiting B, Roy RS, Eiermann GJ, Beconi MG, Biftu T, Chan CC, Edmondson S, Feeney WP, He H, Ippolito DE, Kim D, Lyons KA, Ok HO, Patel RA, Petrov AN, Pryor KA, Qian X, Reigle L, Woods A, Wu JK, Zaller D, Zhang X, Zhu L, Weber AE, Thornberry NA. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005 Oct; 54(10):2988-94.
- ↑ Kao DP. What can we learn from drug marketing efficiency? BMJ (Clinical research ed.). 2008; 337:a2591.(Epub)
- ↑ Rachman J, Barrow BA, Levy JC, Turner RC. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia. 1997 Feb; 40(2):205-11.
- ↑ Deacon CF, Hughes TE, Holst JJ. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes. 1998 May; 47(5):764-9.
- ↑ Thornberry, NA, Weber AE. Discovery of JANUVIA™ (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes
- ↑ Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, Hickey GJ, Kowalchick JE, Leiting B, Lyons K, Marsilio F, McCann ME, Patel RA, Petrov A, Scapin G, Patel SB, Roy RS, Wu JK, Wyvratt MJ, Zhang BB, Zhu L, Thornberry NA, Weber AE. (2R)-4-oxo-4-3-(trifluoromethyl)-5,6-dihydro1,2,4.triazolo4,3-a.pyrazin-7(8H)-yl.-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Journal of medicinal chemistry. 2005 Jan 13; 48(1):141-51.(Link to article – subscription may be required.)
- ↑ Herman G, Hanefeld M, Wu M, Chen X, Zhao P, Stein P, Effect of MK-0431, a dipeptidyl peptidase IV (DPP-IV) inhibitor, on glycemic control after 12 weeks in patients with type 2 diabetes. Diabetes 2005, 54(S1), A134.
- ↑ Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clinical pharmacology and therapeutics. 2005 Dec; 78(6):675-88.(Link to article – subscription may be required.)
- ↑ Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clinical therapeutics. 2006 Jan; 28(1):55-72.(Link to article – subscription may be required.)
- ↑ Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA. Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. Journal of clinical pharmacology. 2006 Aug; 46(8):876-86.(Link to article – subscription may be required.)
- ↑ Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clinical therapeutics. 2006 Oct; 28(10):1556-68.(Link to article – subscription may be required.)
- ↑ Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes care. 2006 Dec; 29(12):2638-43.(Link to article – subscription may be required.)
- ↑ Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes, obesity & metabolism. 2007 Sep; 9(5):733-45.(Link to article – subscription may be required.)
