Repaglinide

Last updated
Repaglinide
Repaglinide.svg
Repaglinide ball-and-stick.png
Clinical data
Trade names Prandin, Novonorm, Enyglid, others
AHFS/Drugs.com Monograph
MedlinePlus a600010
License data
Pregnancy
category
  • AU:C
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 56% (oral)
Protein binding >98%
Metabolism Liver oxidation and glucuronidation (CYP3A4-mediated)
Elimination half-life 1 hour
Excretion Fecal (90%) and kidney (8%)
Identifiers
  • (S)-2-Ethoxy-4-(1-[2-{piperidin-1-yl}phenyl]-3-methylbutylcarbamoylmethyl)benzoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.158.190 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H36N2O4
Molar mass 452.595 g·mol−1
3D model (JSmol)
Melting point 126 to 128 °C (259 to 262 °F)
  • O=C(O)c1ccc(cc1OCC)CC(=O)N[C@H](c2ccccc2N3CCCCC3)CC(C)C
  • InChI=1S/C27H36N2O4/c1-4-33-25-17-20(12-13-22(25)27(31)32)18-26(30)28-23(16-19(2)3)21-10-6-7-11-24(21)29-14-8-5-9-15-29/h6-7,10-13,17,19,23H,4-5,8-9,14-16,18H2,1-3H3,(H,28,30)(H,31,32)/t23-/m0/s1 Yes check.svgY
  • Key:FAEKWTJYAYMJKF-QHCPKHFHSA-N Yes check.svgY
   (verify)

Repaglinide is an antidiabetic drug in the class of medications known as meglitinides, and was invented in 1983. Repaglinide is a medication used in addition to diet and exercise for blood sugar control in type 2 diabetes. [1] The mechanism of action of repaglinide involves promoting insulin release from β-islet cells of the pancreas; like other antidiabetic drugs, a main side effect concern is hypoglycemia. [1] It is sold by Novo Nordisk under the name of Prandin in the United States, Gluconorm in Canada, Surepost in Japan, Repaglinide in Egypt, and Novonorm elsewhere. In Japan it is produced by Dainippon Sumitomo Pharma. [2] [ failed verification ]

Contents

Medical uses

Repaglinide is an oral medication used in addition to diet and exercise for blood sugar control in type 2 diabetes. [1]

Contraindications

Repaglinide is contraindicated in people with:

  1. Diabetic ketoacidosis, with or without coma
  2. Type 1 diabetes
  3. Co-administration with gemfibrozil
  4. Known hypersensitivity to drug or inactive ingredients [1]

Adverse events

Common adverse events include: [1]

Metabolic

Respiratory

Gastrointestinal

Musculoskeletal

Other

Serious adverse events include: [1]

Special populations

Pregnancy category C: safety in pregnant women has not been established. [1] Data is limited, and there is only one case report that notes no complications with the use of repaglinide during pregnancy. [3]

Caution should be taken in people with liver disease and decreased kidney function when using this medication. [1]

Drug interactions

Repaglinide is a major substrate of CYP3A4 and should not be administered concomitantly with gemfibrozil, clarithromycin or azole antifungals such as itraconazole or ketoconazole. [1] Administration of both repaglinide and one or more of these drugs results in an increase in plasma concentration of repaglinide and may lead to hypoglycemia. Co-administration of repaglinide and clopidogrel (a CYP2C8 inhibitor) may lead to a significant decrease in blood glucose levels due to a drug-drug interaction. [4] In fact, using these drugs together for even one day can cause repaglinide levels to increase over 5-fold...and may lead to significant hypoglycemia. Repaglinide should not be combined with sulfonylurea, because they have the same mechanism of action. [1]

Pharmacology

Mechanism of action

Repaglinide lowers blood glucose by stimulating the release of insulin from the beta islet cells of the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion. [1]

Pharmacokinetics

Absorption: repaglinide has a 56% bioavailability when absorbed from the gastrointestinal tract. Bioavailability is reduced when taken with food; the maximum concentration decreases by 20%.

Distribution: The protein binding of repalglinide to albumin is greater than 98%.

Metabolism: repaglinide is primarily metabolized by the liver - specifically CYP450 2C8 and 3A4 - and to a lesser extent via glucuronidation. Metabolites of repaglinide are inactive and do not display glucose-lowering effects.

Excretion: repaglinide is 90% excreted in the feces and 8% in the urine. 0.1% is cleared unchanged in the urine. Less than 2% is unchanged in the feces. [1]

History

Precursor drugs to repaglinide were invented in late 1983 by scientists at Dr Karl Thomae GmbH, a German drug manufacturer located at Biberach an der Riß in southern Germany which was acquired by Boehringer Ingelheim in 1990. The drug that became repaglinide was later licensed by Boehringer to Novo Nordisk, which filed an Investigational New Drug application for the compound with the Food and Drug Administration (FDA) in April 1992. Novo Nordisk filed its New Drug Application (NDA) for Prandin in July 1997 and it was quickly approved, gaining FDA approval in December 1997. The drug was the first of the meglitinide class. It was branded Prandin because its quick onset and short duration of action concentrates its effect around meal time (the prandium was the Roman meal which is comparable to the modern lunch). [2]

Intellectual property

After several attempts to file for U.S. patent protection, a filing was made in March 1990 which eventually became U.S. Patents 5,216,167 (June 1993), 5,312,924 (May 1994) and 6,143,769 (November 2000). After filing its NDA for repaglinide in 1997, Novo Nordisk applied for patent extension under the Hatch-Waxman Act. This process, called patent term restoration, allows drug patents to be extended based on the time that a drug spent in clinical trials and in the approval process. Previously it had been decided by the U.S. Patent and Trademark Office that the expiration date of U.S. Patents 5,216,167 and 5,312,924 would be 5 September 2006. In February 2001 Prandin's patent life was extended to 14 March 2009 in response to Novo Nordisk's patent term restoration application, with U.S. Patent 5,216,167 having been reissued as RE37035. [5]

Prior to the end of repaglinide's patent term, Novo Nordisk obtained a new patent, U.S. Patent 6,677,358 (January 2004), covering the combination therapy of repaglinide together with the generic anti-diabetic drug metformin. This new patent was due to expire June 2018. In January 2011, a federal court ruled Novo Nordisk's new patent invalid on the grounds of obviousness, and unenforceable on the grounds of inequitable conduct on the part of Novo Nordisk's patent attorneys. [6]

Related Research Articles

<span class="mw-page-title-main">Hypoglycemia</span> Health condition

Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal. Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death. Symptoms typically come on quickly.

The following is a glossary of diabetes which explains terms connected with diabetes.

<span class="mw-page-title-main">Glipizide</span> Chemical compound

Glipizide, sold under the brand name Glucotrol among others, is an anti-diabetic medication of the sulfonylurea class used to treat type 2 diabetes. It is used together with a diabetic diet and exercise. It is not indicated for use by itself in type 1 diabetes. It is taken by mouth. Effects generally begin within half an hour and can last for up to a day.

<span class="mw-page-title-main">Glimepiride</span> Group of stereoisomers

Glimepiride is an antidiabetic medication within the sulfonylurea class, primarily prescribed for the management of type 2 diabetes. It is regarded as a second-line option compared to metformin, due to metformin's well-established safety and efficacy. Use of glimepiride is recommended in conjunction with lifestyle modifications such as diet and exercise. It is taken by mouth, reaching a peak effect within three hours and lasting for about a day.

Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exception of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.

<span class="mw-page-title-main">Insulinoma</span> Medical condition

An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a minority metastasize. Insulinomas are one of the functional pancreatic neuroendocrine tumour (PNET) group. In the Medical Subject Headings classification, insulinoma is the only subtype of "islet cell adenoma".

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

<span class="mw-page-title-main">Hyperinsulinism</span> Medical condition

Hyperinsulinism refers to an above normal level of insulin in the blood of a person or animal. Normal insulin secretion and blood levels are closely related to the level of glucose in the blood, so that a given level of insulin can be normal for one blood glucose level but low or high for another. Hyperinsulinism can be associated with several types of medical problems, which can be roughly divided into two broad and largely non-overlapping categories: those tending toward reduced sensitivity to insulin and high blood glucose levels (hyperglycemia), and those tending toward excessive insulin secretion and low glucose levels (hypoglycemia).

<span class="mw-page-title-main">Diazoxide</span> Medication used to treat low blood sugar and high blood pressure

Diazoxide, sold under the brand name Proglycem and others, is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in refractory cases of sulfonylurea toxicity. It is generally taken by mouth.

<span class="mw-page-title-main">Glibenclamide</span> Chemical compound

Glibenclamide, also known as glyburide, is an antidiabetic medication used to treat type 2 diabetes. It is recommended that it be taken together with diet and exercise. It may be used with other antidiabetic medication. It is not recommended for use by itself in type 1 diabetes. It is taken by mouth.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

<span class="mw-page-title-main">Streptozotocin</span> Chemical compound

Streptozotocin or streptozocin (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain cancers of the islets of Langerhans and used in medical research to produce an animal model for hyperglycemia and Alzheimer's in a large dose, as well as type 2 diabetes or type 1 diabetes with multiple low doses.

<span class="mw-page-title-main">Meglitinide</span> Chemical substance

Meglitinides or glinides are a class of drugs used to treat type 2 diabetes.

<span class="mw-page-title-main">Nateglinide</span> Chemical compound

Nateglinide is a drug for the treatment of type 2 diabetes. Nateglinide was developed by Ajinomoto, a Japanese company and sold by the Swiss pharmaceutical company Novartis.

<span class="mw-page-title-main">Insulin (medication)</span> Use of insulin protein and analogs as medical treatment

As a medication, insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose. Such conditions include type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. Insulin is also used along with glucose to treat hyperkalemia. Typically it is given by injection under the skin, but some forms may also be used by injection into a vein or muscle. There are various types of insulin, suitable for various time spans. The types are often all called insulin in the broad sense, although in a more precise sense, insulin is identical to the naturally occurring molecule whereas insulin analogues have slightly different molecules that allow for modified time of action. It is on the World Health Organization's List of Essential Medicines. In 2020, regular human insulin was the 307th most commonly prescribed medication in the United States, with more than 1 million prescriptions.

<span class="mw-page-title-main">Insulin degludec</span> Ultralong-acting basal insulin analogue

Insulin degludec (INN/USAN) is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. It is administered via subcutaneous injection once daily to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 42 hours, making it a once-daily basal insulin, that is one that provides a base insulin level, as opposed to the fast- and short-acting bolus insulins.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that modulate sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. As of 2014, several medications of this class had been approved or were under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It was developed by Novo Nordisk in 2012 and approved for use in the US in 2017. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold under the brand names Ozempic (injectable) and Rybelsus (pill) for diabetes, and under the brand name Wegovy for weight loss.

Insulin glargine/lixisenatide, sold under the brand name Soliqua 100/33 among others, is a fixed-dose combination medication that combines insulin glargine and lixisenatide and is used to treat diabetes.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "DailyMed - Repaglinide - repaglinide tablet". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  2. 1 2 "Welcome to Novo Nordisk A/S". Novo Nordisk A/S. Retrieved 2015-11-05.
  3. Mollar-Puchades MA, Martin-Cortes A, Perez-Calvo A, Diaz-Garcia C (January 2007). "Use of repaglinide on a pregnant woman during embryogenesis". Diabetes, Obesity & Metabolism. 9 (1): 146–7. doi:10.1111/j.1463-1326.2006.00629.x. PMID   17199735. S2CID   34476970.
  4. "Gluconorm (repaglinide) - New Contraindication for Concomitant Use with Clopidogrel". Health Canada. 25 August 2021.
  5. "Details for Patent: RE37035".
  6. Frankel A (2011-01-27). "Judge Finds Novo Nordisk Diabetes Drug Patent Invalid and Unenforceable, Questions In-House Patent Lawyer's Conduct" . Retrieved 2011-02-05.