Methylnaltrexone
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Methylnaltrexone, MNTX (trade name Relistor ® , a product of Wyeth ) is a drug for the treatment of drug-against moderate to highest pain , known as opioids , induced constipation ( constipation ). It is used in the advanced stages of the disease, when the effect of the usual laxatives is insufficient.
Methylnaltrexone is a quaternary derivative of the opioid antagonist naltrexone and the first representative of a new active principle for the causal therapy of opioid-induced constipation . : Opioid-Induced Constipation (OIC)}.
Clinical information
In the application of potent opioid - analgesics in the palliative pain therapy , the opioid-induced constipation . A great clinical challenge Spastic constipation the intestine (constipation) are determined by the stimulation of μ-receptors of the myenteric plexus of the gut wall with a constriction of the smooth Muscles . They are the most relevant side effect in long-term pain treatment and - in contrast to other opioid-related side effects - are subject to only a low level of tolerance development (strong habituation to opioids with a dose increase of up to 20 times).
Application areas (indications)
Treatment of patients in advanced stages of the disease who receive palliative treatment and long-term therapy with drugs from the group of active substances called opioids, which trigger opioid-induced constipation and the response to conventional laxative therapy is inadequate. MNTX is given in addition to the laxative.
Dosis, kind and Time of the Use
Methylnaltrexone is given subcutaneously . The dosage depends on the patient's body weight, it is usually 8 mg of the active ingredient for patients weighing 38 to 61 kg, or 12 mg for patients weighing 62 to 114 kg. The dose is given as an injection under the skin every 48 hours, either in the thigh, abdomen (stomach) or upper arm. Age-related dose adjustment is not necessary and MNTX can be used with or without meals.
The effect of MNTX has been studied in patients with opioid-induced constipation and is not indicated in non-opioid-induced constipation.
Contraindications (contraindications)
The use of methylnaltrexone bromide in patients with known or suspected mechanical gastrointestinal obstruction, such as intestinal obstruction (ileus), and in an acute surgical abdomen , is contraindicated, as is hypersensitivity to the active ingredient.
Use during pregnancy and breastfeeding
There is no experience with adequate data from the use of methylnaltrexone bromide in pregnancy . Animal studies have shown reproductive toxicity at high doses . The potential risk for humans is unknown. If possible, Relistor should not be used during pregnancy.
It is not known whether the active substance is excreted in breast milk during breastfeeding . Animal studies have shown that methylnaltrexone bromide is excreted in breast milk.
Special patient groups
Treatment with Relistor is not recommended in patients with severe hepatic impairment or dialysis patients with end-stage renal impairment as no data are available. The drug should not be used to treat children and adolescents under 18 years of age, as there is insufficient experience in this age group.
Adverse effects (side effects)
In all subjects who participated in placebo-controlled studies , the side effects associated with the medicine were as follows: the most common symptoms were abdominal pain, nausea , diarrhea, and flatulence (wind). Often been Vertigo (dizziness), and general discomfort at the injection site, such as stinging, burning, pain, redness, edema observed.
Pharmacological properties
Mechanism of action (pharmacodynamics)
Methylnaltrexone bromide is a competitive antagonist of opioid binding at the µ-opioid receptor . In-vitro studies showed that methylnaltrexone at the µ-receptor has an inhibition constant of K i = 28 nM, with an 8-fold lower effect on κ-opioid receptors ( K i = 203 nM) and a greatly reduced affinity for δ-opioid receptors . Since it is a strongly polar quaternary amine with a pronounced hydrophilic character , methylnaltrexone is not able to cross the blood-brain barrier into the highly fatty tissue of the brain . This allows methylnaltrexone, as a peripherally acting antagonist of the µ-opioid receptor in tissues such as the digestive tract, to develop its effect selectively without influencing the analgesic effect in the central nervous system .
Absorption and distribution in the body (pharmacokinetics)
Absorption : After subcutaneous injection, methylnaltrexone bromide is rapidly absorbed and peak concentrations are reached after approximately 0.5 hours. The AUC and the AUC increase in proportion to the dose when the dose is increased from 0.15 mg / kg to 0.5 mg / kg. The absolute bioavailability of a subcutaneous 0.30 mg / kg dose compared to an intravenous 0.30 mg / kg dose is 82%. Distribution : Methylnaltrexone is subject to low tissue distribution. The volume of distribution in the "steady state" is around 1.1 liters / kg. The plasma protein binding of methylnaltrexone is low, 11.0% to 15.3%. Metabolism : Methylnaltrexone is only moderately metabolized based on the amount of metabolites that are found in the excrement . The biotransformation to methyl-6-naltrexol isomers and methylnaltrexone sulfate appears to be the primary pathway of metabolism. Each of the methyl-6-naltrexol isomers has a somewhat lower antagonistic activity than the parent compound and, with about 8% of the drug-related substances, is low in plasma. Methylnaltrexone sulfate is an inactive metabolite and accounts for around 25% of drug-related substances in plasma. N- demethylation of methylnaltrexone to form naltrexone is insignificant and accounts for 0.06% of the given dose. Elimination : Methylnaltrexone is mainly excreted as unchanged active substance. About half of the dose is excreted renally in the urine and a little less in the faeces . The terminal half-life t 1/2 of availability is approximately 8 hours.
Other Information
Chemical and pharmaceutical information
The quaternary ammonium compound with bromide as counterion and the international non- proprietary name methylnaltrexonium bromide is used exclusively as a medicinal substance . It is the N- methylated derivative of the centrally and peripherally active antagonist naltrexone. The methylation significantly increases the polarity of the molecule and gives it a hydrophilic character .
Development and marketing
MNTX-like drugs were first synthesized by the chemists Leon I. Goldberg (USA), Herbert Merz (DE) and Klaus Stockhaus (DE) and in 1979 by Boehringer Ingelheim (DE) as a patent with the title: Quaternary derivatives of noroxymorphone which relieve intestinal immobility published.
The American Wyeth Pharmaceuticals Inc., a division of the world's tenth largest pharmaceutical company Wyeth, announced on December 23, 2005 that it had entered into an agreement with Progenics Pharmaceuticals Inc. to develop and market methylnaltrexone, a drug against gastrointestinal complaints Has. Under the agreement, Wyeth Pharmaceuticals obtained worldwide rights to methylnaltrexone, while Progenics retained an option to co-commercialize the product in the United States. Wyeth made an advance payment of $ 60 million to Progenics, with additional “milestone payments” of up to $ 356.5 million.
At the beginning of July 2008, the European Commission granted marketing authorization for an injection solution containing methylnaltrexone in the European Union . Germany was the first country to introduce the drug. In April 2008, the drug was approved by the Food and Drug Administration (FDA) in the United States .
An oral formulation of MNTX for the treatment of opioid-induced constipation and an intravenous dosage form of MNTX for the treatment of post-operative ileus (POI) are in clinical phase II .
literature
- Ernst Mutschler et al .: Mutschler - drug effects textbook of pharmacology and toxicology . 9th edition. Scientific Verlagsgesellschaft, Stuttgart 2008, ISBN 978-3-8047-1952-1 .
- Patent EP0938316 : Galenic Composition Containing Opioid Antagonists. Released September 1, 1999 .
Web links
- Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Methylnaltrexone
- Overview of the 13 studies by Progenics at ClinicalTrials.gov
- Overview of the 13 studies by Progenics by geographic region at ClinicalTrials.gov
- A Double-Blind, Placebo-Controlled Study of Methylnaltrexone (MNTX) for the Relief of Constipation Due to Chronic Opioid Therapy in Patients with Advanced Medical Illness (PDF file; 209 kB)
- A Three-Month Open-Label Treatment Extension of Protocol MNTX 302. (PDF file; 115 kB)
Individual evidence
- ↑ There is not yet a harmonized classification for this substance . A labeling of Morfinan, 17- (ciclopropilmetil) -4,5-epossi-3,14-diidrossi-17-metil-6-osso-, bromuro, (5a) - in the Classification and Labeling is shown, which is derived from a self-classification by the distributor Inventory of the European Chemicals Agency (ECHA), accessed on 7 July 2020.
- ↑ Holzer P .: Treatment of opioid-induced gut dysfunction. Expert Opin Investig Drugs . 2007 Feb; 16 (2): 181-94. PMID 17243938
- ↑ Freye E, Latasch L: Development of tolerance under opioid administration - molecular mechanisms and clinical significance. Anesthesiol Intensivmed Emergency Med Schmerzther. 2003 Jan; 38 (1): 14-26. PMID 12522725
- ↑ Shaiova L et al. A review of methylnaltrexone, a peripheral opioid receptor antagonist, and its role in opioid-induced constipation. Palliat Support Care. 2007 Jun; 5 (2): 161-6. PMID 17578067
- ↑ a b c Relistor: Summary of Product Characteristics, as of July 2008 on the website of the European Medicines Agency (EMEA)
- ↑ Yuan CS et al .: Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther . 1996 Apr; 59 (4): 469-75. PMID 8612393
- ↑ a b Page no longer available , search in web archives: English technical information for Relistor 12 mg / 0.6 ml injection solution from Wyeth-USA - Information as of April 2008 ( page no longer available , search in web archives ) Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.
- ↑ Yuan CS. et al .: Effects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: a double-blind randomized placebo-controlled trial. J Pharmacol Exp Ther . 2002 Jan; 300 (1): 118-23. PMID 11752106 full text HTML
- ↑ Patent US4176186 : Quaternary derivatives of noroxymorphone which relieve intestinal immobility. Published September 27, 1979 .
- ↑ First selective μ-opioid receptor antagonist methylnaltrexone (Relistor®) receives approval for Europe . Wyeth press release July 7, 2008.
- ↑ Progenics and Wyeth Announce FDA has Approved Relistor - First Drug for Opioid-Induced Constipation to Launch in United States ( Memento of the original from September 17, 2017 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. . Wyeth press release dated April 24, 2008, accessed September 17, 2017.
