Prucalopride (Brand Name Resolor)

Prucalopride Basic Facts:

• Brand name Resolor - developed by Movetis.
• New drug for treatment of constipation.
• Acts as a selective, high affinity 5-HT4 receptor agonist.
• Targets the impaired motility associated with chronic constipation - leading to a normalisation of bowel movements.
• Indicated for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief.
• Median time to the first spontaneous bowel movement is 2 1/2 hours.

Actions:

• First in class dihydrobenzofurancarboxamide.
• Selective, high affinity serotonin (5-HT4) receptor agonist.
• Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation.
• The 5-HT4 receptor stimulation induces colonic mass movements.
• Prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors - differentiating it from tegaserod & cisapride.

Pharmacokinetics:

• Prucalopride is rapidly absorbed & extensively distributed.
• Elimination is mainly unchanged in the urine.
• The renal excretion of unchanged prucalopride involves both passive filtration & also active secretion.
• Plasma clearance averages 317 ml/min.
• Terminal half-life is 24–30 hours.
• Steady-state drug concentrations are reached within 3–4 days.

Dosing:

• 2 mg once daily.
• Exceeding the daily dose of 2 mg is not expected to increase efficacy.

Drug Interactions:

• Low interaction potential.
• Therapeutic concentrations of prucalopride do not affect the CYP-mediated metabolism of drugs.

Side Effects:

• Most common are headache & gastrointestinal symptoms.
• GI symptoms - Abdominal pain, diarrhoea, nausea - about 20% patients.
• These effects occur mostly at the start of therapy and tend to disappear within a few days.
• Prucalopride has no significant effect on QT interval.

Tags: 5-HT4 receptor antagonist - Constipation - Prucalopride - Resolor - Serotonin
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Liraglutide (Brand Name Victoza)

General Liraglutide Facts:

• Liraglutide (NN2211).
• Marketed under the brand name Victoza.
• Developed by Novo Nordisk for the treatment of type 2 diabetes.
• Approved by the European Medicines Agency (EMEA) on July 3, 2009.
• Approved by the U.S. Food and Drug Administration (FDA) on January 25, 2010.

Chemistry:

• Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist.
• It has 97% amino acid sequence homology to endogenous human GLP-1(7-37).

Actions & Pharmacodynamics:

• Long-acting glucagon-like peptide-1 (GLP-1) analog.
• GLP-1(7-37) represents <20%>
• Liraglutide improves control of blood glucose.[4]
• It reduces meal-related hyperglycemia (for 12 hours after administration).
• It increases insulin secretion, delays gastric emptying, & suppresses prandial glucagon secretion.
• It lowers blood triglyceride levels.
• Liraglutide like GLP-1(7-37), activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein (Gs) in pancreatic beta cells.
• Liraglutide thus increases beta cell intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations.
• The insulin secretion reduces as blood glucose concentrations fall & approach euglycemic levels.
• Glucagon secretion is also decreased by liraglutide in a glucose-dependent manner.
• The mechanism of blood glucose lowering also involves a delay in gastric emptying.
• As liraglutide acts in a glucose-dependent manner, it shows negligible risk of hypoglycemia.
• Liraglutide also decreases appetite & maintains body weight.[3]

Pharmacokinetics:

• GLP-1(7-37) has a half-life of 1.5–2 minutes due to degradation by dipeptidyl peptidase IV (DPP-IV) & neutral endopeptidases (NEP).
• Liraglutide is stable against metabolic degradation by the above described peptidases giving a much longer plasma half-life of 13 hours following subcutaneous administration.

ADRs (Side Effects):

• Liraglutide has only mild & transient side effects, mainly gastrointestinal.
• Possible cancer risk (see below).

ADRs - Cancer:

• Review by the FDA advisory panel (April 2, 2009) regarding the significance of malignant C-cell carcinoma & thyroid C-cell focal hyperplasia in rats & mice.
• Victoza has a Black Box Warning, "Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk".[1]
• The FDA have noted that serum calcitonin was slightly increased in liraglutide patients but still within normal ranges.
• Ongoing monitoring for 15 years in a cancer registry has been instituted.[2]

Dosing:

• The Victoza pen comes in doses of 0.6 mg, 1.2 mg, & 1.8 mg.
• Given once a day, at any time, independent of meals.
• Best to be injected around the same time of day, once the most convenient time of day has been found.
• Subcutaneous injection in abdomen, thigh or upper arm.
• Recommended starting dose is 0.6 mg once daily.
• After at least one week, the dose should be increased to a maintenance dose of 1.2 mg.
• Some patients may benefit from an increase in dose from 1.2 mg to 1.8 mg, based on clinical response after at least one week on 1.2 mg dosing.

Dosing - Combination Therapies:

• Metformin - No dose adjustment.
• Metformin + thiazolidinedione - No dose adjustment.
• Sulphonylurea - Sulphonylurea dose adjustment may be needed to reduce risk of hypoglycaemia.
• Metformin + sulphonylurea - Sulphonylurea dose adjustment may be needed to reduce risk of hypoglycaemia.

References:

1] - Victoza Package Insert Date of Issue: January 2010 Version: 1

2] - N Engl J Med, 362:774

3] - Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes. Diabetes Care. Oct 2008

4] - http://diabetes.webmd.com/news/20080924/new-diabetes-drug-liraglutide-works (Sept 2008)

Tags: Cancer - Diabetes Mellitus - EMEA - GLP-1 - GLP-1(7-37) - Glucagon-like peptide-1 - Hypoglycaemia - Insulin - Liraglutide - Metformin - Novo Nordisk - Peptidase - Sulphonylurea - Victoza

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