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Pronunciation | /pæləˈnoʊsətrɒn/ pal-ə-NOH-sə-tron |
Trade names | Aloxi |
AHFS/Drugs.com | Monograph |
MedlinePlus | a610002 |
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Routes of administration | Intravenous, by mouth |
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Pharmacokinetic data | |
Bioavailability | 97% (oral) |
Protein binding | 62% |
Metabolism | Liver, 50% (mostly CYP2D6-mediated, CYP3A4 and CYP1A2 also involved) |
Elimination half-life | Approximately 40–50 hours |
Excretion | Kidney, 80% (of which 49% unchanged); fecal (5 to 8%) |
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Chemical and physical data | |
Formula | C19H24N2O |
Molar mass | 296.414 g·mol−1 |
3D model (JSmol) | |
Specific rotation | [α]D −136° [α]D –94.1° (HCl) |
Melting point | 87 to 88 °C (189 to 190 °F) |
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Palonosetron, sold under the brand name Aloxi, is a medication used for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). [2] [4] [5] It is a 5-HT3 antagonist. [2] [4] [5]
Palonosetron is administered intravenously, [6] or as a single oral capsule. [7] It has a longer duration of action than other 5-HT3 antagonists. The oral formulation was approved on August 22, 2008, for prevention of acute CINV alone, as a large clinical trial did not show oral administration to be as effective as intravenous use against delayed CINV. [7] It is on the World Health Organization's List of Essential Medicines. [8]
The oral combination netupitant/palonosetron is approved for both acute and delayed CINV. [9] [10] [11] [12]
The most common adverse effects are headache, which occurs in 4–11% of patients, and constipation in up to 6% of patients. In less than 1% of patients, other gastrointestinal disorders occur, as well as sleeplessness, first- and second-degree atrioventricular block, muscle pain and shortness of breath. Palonosetron is similarly well tolerated as other 5-HT3 antagonists, and slightly less than placebo. [13] [14]
Palonosetron does not relevantly inhibit or induce cytochrome P450 liver enzymes. There are case reports about serotonin syndrome when the drug is combined with serotonergic substances such as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), two common types of antidepressants. [13] [14]
Palonosetron is a 5-HT3 antagonist, commonly known as a setron. These drugs act by blocking serotonin from binding to the 5-HT3 receptor. [15]
Orally taken palonosetron is absorbed well from the gut and has a bioavailability of 97%. Highest blood plasma levels are reached after 5.1±1.7 hours, independently of food intake, and plasma protein binding is 62%. 40% of the substance are eliminated in the unchanged form, and a further 45–50% are metabolized by the liver enzyme CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2. The two main metabolites, the N-oxide and a hydroxy derivative, have less than 1% of palonosetron's antagonistic effect and are thus practically inactive. [13] [14]
Palonosetron and its metabolites are mainly (to 80–93%) eliminated via the kidney. Biological half-life in healthy persons was 37±12 hours in a study, and 48±19 hours in cancer patients. In 10% of patients, half-life is over 100 hours. [13] [14] Most other marketed setrons have half-lives in the range of about two to 15 hours.
The substance is solid at room temperature and melts at 87 to 88 °C (189 to 190 °F). [16] The infusions and capsules contain palonosetron hydrochloride, [13] which is also a solid. The hydrochloride is easily soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and isopropyl alcohol. [14] [17]
The molecule has two asymmetric carbon atoms. It is used in form of the pure (S,S)-stereoisomer. [17]
Palonosetron was developed by Helsinn around 2001. In January 2003, Helsinn filed a provisional patent application on palonosetron. Over the next 10 years, Helsinn filed four patent applications that claimed priority to the January 2003 date. Relevant here, Helsinn filed its fourth patent application in 2013. That patent (the ’219 patent) covers a fixed dose of 0.25 mg of palonosetron in a 5 ml solution. While developing the drug, Helsinn entered into a confidential licensing agreement with a company called MGI to sell palonosetron in the United States. This licensing agreement contained chemical information about palonosetron and dosage requirements. However, Helsinn did not file for a patent on palonosetron until two years after they had signed their agreement with MGI.
In 2011 Teva Pharmaceuticals - a generic drug manufacturer- challenged the validity of Helsinn's patent(s) by filing an application for a generic version of palonosetron with the FDA. Teva claimed that, because Helsinn disclosed/sold the 0.25 mg dose of palonosetron to MGI in 2003, which is more than a year (actually about 2 years) before the priority date of its '219 patent, this "secret" sale barred Helsinn from receiving a patent. This conclusion results from the language of the America Invents Act, which bars patents on inventions, which were “in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention,” 35 U. S. C. §102(a)(1).
The District Court held that the AIA's “on sale” provision did not apply, because the public disclosure of the agreements did not disclose the 0.25 mg dose. The Federal Circuit reversed, holding that the sale was publicly disclosed, regardless of whether the details of the invention were publicly disclosed in the terms of the sale agreements. The SCOTUS agreed with the Federal Circuit, that in this case a commercial sale to a third party, who is required to keep the invention confidential, nevertheless placed the invention “on sale” under USC §102(a).
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be used for severe cases of gastroenteritis, especially if the patient is dehydrated.
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Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease. It is also used to treat migraine headaches.
Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.
Buspirone, sold under the brand name Buspar, among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. It is a serotonin 5-HT1A receptor agonist, increasing action at serotonin receptors in the brain. It is taken orally, and takes two to six weeks to be fully effective.
Fexofenadine, sold under the brand name Allegra among others, is an antihistamine pharmaceutical drug used in the treatment of allergy symptoms, such as hay fever and urticaria.
Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, migraines or surgery. It is also effective for treating gastroenteritis. It can be given orally, intramuscularly, or intravenously.
Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in females only.
Dolasetron (trade name Anzemet) is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when symptoms are due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.
Tamsulosin, sold under the brand name Flomax among others, is a medication used to treat symptomatic benign prostatic hyperplasia (BPH) and chronic prostatitis and to help with the passage of kidney stones. The evidence for benefit with a kidney stone is better when the stone is larger. Tamsulosin is taken by mouth.
The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.
Metopimazine, sold under the brand names Vogalen and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting. It is marketed in Europe, Canada, and South America. As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.
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Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the patient, and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles.
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Netupitant/palonosetron, sold under the brand name Akynzeo, is a fixed-dose combination medication used for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. It is marketed and distributed by Helsinn Therapeutics. Netupitant is an NK1 receptor antagonist and palonosetron is a 5-HT3 receptor antagonist.