1. DB08900
TEDUGLUTIDE
C164H252N44O55S
3.7 KDa
CATEGORY
HORMONE ANALOGUE

2. DESCRIPTION
Teduglutide is a glucagon-like peptide-2 (GLP-2) analogue. It is made up of 33 amino acids and is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. Teduglutide differs from GLP-2 by one amino acid (alanine is substituted by glycine). The significance of this substitution is that teduglutide is longer acting than endogenous GLP-2 as it is more resistant to proteolysis from dipeptidyl peptidase-4. FDA approved on December 21, 2012.
INDICATION
Treatment of short bowel syndrome (SBS), malabsorption associated with the removal of the intestine, in adults patients who are dependent on parenteral support.
PHARMACODYNAMICS
An enhancement of gastrointestinal fluid absorption ( mL/day) was observed following daily administrations of teduglutide. An increase in villus height and crypt depth of the intestinal mucosa was also noted. A decrease in fecal weight has also been observed. Teduglutide does not prolong the QTc interval.

3. MECHANISM OF ACTION
Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by L-cells of the distal intestine in response to meals. GLP-2 increases intestinal and portal blood flow and inhibit gastric acid secretion. Teduglutide binds to the glucagon-like peptide-2 receptors located in enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. This causes the release of insulin-like growth factor (IGF)-1, nitric oxide and keratinocyte growth factor (KGF). These growth factors may contribute to the increase in crypt cell growth and surface area of the gastric mucosa. Ultimately, absorption through the intestine is enhanced.
TOXICITY
The most common adverse reactions across all studies with GATTEX are abdominal pain, injection site reactions, nausea, headaches, abdominal distension, upper respiratory tract infection. In addition, vomiting and fluid overload were reported in the SBS studies (1 and 3) at rates.

4. METABOLISM
Although a formal investigation has not been conducted, it is expected because teduglutide is a peptide-based drug, it will be degraded into smaller peptides and amino acids via catabolic pathways. The cytochrome P450 enzyme system is not involved in the metabolism of this drug.
ABSORPTION
The pharmacokinetic profile of teduglutide (when administered subcutaneously) is described by a one-compartment model with first order absorption in the abdomen, arm, and thigh. With escalating doses, teduglutide demonstrates linear pharmacokinetics. Absolute bioavailability, SubQ = 88%; Tmax, SubQ = 3-5 hours; Cmax, 0.05 mg/kg SubQ, SBS patients = 36 ng/mL; AUC, 0.05 mg/kg SubQ, SBS patients = 0.15 µg•hr/mL; Teduglutide does not accumulate following multiple subcutaneous administrations.

5. HALF-LIFE
Terminal half-life, healthy subjects = 2 hours; Terminal half-life, SBS patients = 1.3 hours
ROUTE OF ELIMINATION
Route of elmination was not determined.
VOLUME OF DISTRIBUTION = Vd, healthy subjects = 103 mL/kg
CLEARANCE = Plasma clearance, healthy subjects = 123 mL/hr/kg;This value indicates that teduglutide is primarily cleared by the kidney.
PATENT
Country Patent Number Approved Expires (estimated)
United States
United States
United States
SEQUENCE
HGDGSFSDEMNTILDNLAARDFINWLIQTKITD
TARGETS
Glucagon-like peptide 2 receptor

6. GATTEX (NPS Pharma) REVESTITE (Nycomed)
Subcutaneous
DESCRIPTION
Analogue of human glucagon-like peptide 2, a protein that helps to rehabilitate the intestinal lining. approved for adults with short-bowel syndrome who require parenteral nutrition
NPS Pharmaceuticals has priced its Gattex drug for short bowel syndrome, or SBS, at $295,000, expecting to make peak sales of $350 million from the 3,000-5,000 Americans suffering from this rare disease. SBS causes malabsorption when a significant portion of the small intestine is removed as a result of Crohn's disease, trauma, cancer or other conditions. It is a debilitating disease that urgently needed a focus therapy -- the question, however, is: Is that therapy worth more than a quarter-million dollars to the suffering patient?

7. ADVANTAGE
Degradation resistant GLP-2 analog. Teduglutide [Gly] GLP-2 (GattexTM, NPS Pharmaceuticals, Bedminster, NJ), a DPPIV-resistant analog of GLP-2 lacking
the N-terminal DPPIV cleavage site
VARIATION
Teduglutide is a glucagon-like peptide-2 (GLP-2) analogue. It is made up of 33 amino acids and is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. Teduglutide differs from GLP-2 by one amino acid (alanine is substituted by glycine). The significance of this substitution is that teduglutide is longer acting than endogenous GLP-2 as it is more resistant to proteolysis from dipeptidyl peptidase-4. FDA approved on December 21, 2012
HALF-LIFE
Terminal half-life in healthy subjects = 2 hours
Terminal half-life in SBS patients = 1.3 hours
CLEARANCE
0.05 mg/kg per day

8. ADVERSE REACTION
Risk Evaluation and Mitigation Strategy (REMS) is required because of elevated risks of intestinal cancer and polyps, intestinal obstructions, gallbladder disease, biliary tract disease, and pancreatic disease. Based upon the pharmacodynamic effect of GATTEX, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index.
REFERENCES
Burness CB, McCormack PL: Teduglutide: A Review of its Use in the Treatment of Patients with Short Bowel Syndrome. Drugs Jun 1