Paliperidone

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Structural formula
Structural formula of paliperidone
1: 1 mixture ( racemate )
of ( R ) -isomer (top) and ( S ) -isomer (bottom)
General
Non-proprietary name Paliperidone
other names
  • ( RS ) -3- {2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino] ethyl} -9-hydroxy-2-methyl-6,7,8,9-tetrahydro- 4 H -pyrido [1,2- a ] pyrimidin-4-one
  • (±) -3- {2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino] ethyl} -9-hydroxy-2-methyl-6,7,8,9-tetrahydro- 4 H -pyrido [1,2- a ] pyrimidin-4-one
Molecular formula C 23 H 27 FN 4 O 3
External identifiers / databases
CAS number 144598-75-4
EC number 620-493-1
ECHA InfoCard 100.117.604
PubChem 115237
ChemSpider 103109
DrugBank DB01267
Wikidata Q423292
Drug information
ATC code

N05 AX13

Drug class

Atypical neuroleptic

properties
Molar mass 426.48 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
06 - Toxic or very toxic

danger

H and P phrases H: 301
P: 301 + 310
Toxicological data

65 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Paliperidone is a drug from the group of atypical neuroleptics . It has been approved in the European Union for the treatment of schizophrenia since 2007 under the trade name Invega ( Janssen Pharmaceutica ) in the form of prolonged-release tablets and as Xeplion and Trevicta in intramuscular depot form since 2011 .

The administration of the depot form increases the control of the continuous intake of the drug. This is important insofar as neuroleptics are used for the treatment of some severe mental illnesses, but are often discontinued by patients after a while due to lack of insight. At the same time, the depot form simplifies everyday life for those affected, as daily intake and the associated fluctuations in level are eliminated. A disadvantage compared to the tablet form, on the other hand, is the aspect that the active ingredient remains in the blood for a longer time if serious side effects occur and the effect therefore lasts for a longer time.

Clinical information

Paliperidone is the active main metabolite “9-hydroxyrisperidone” of the neuroleptic risperidone . In the human organism, after taking risperidone, its breakdown product paliperidone, which is pharmacologically active, is formed.

With regard to the desired and undesired effects, paliperidone is largely similar to risperidone. However, the manufacturer has not yet published a comparative study ( head-to-head study ).

Paliperidone belongs to the group of me-too preparations .

Pharmacological properties

Mechanism of action (pharmacodynamics)

The mechanism of action has already been partially described for risperidone . Paliperidone binds strongly to serotonin 5-HT 2 - and dopamine D 2 receptors . In addition, paliperidone also blocks α 1 adrenoceptors and, to a lesser extent, histamine H 1 receptors and α 2 adrenoceptors . The pharmacological effect of the (+) - and (-) - paliperidone enantiomers is qualitatively and quantitatively similar.

Absorption and distribution in the body (pharmacokinetics)

The pharmacokinetics of paliperidone are different from risperidone in several ways. Due to the sustained-release form, there is less variation between peak and trough concentrations compared to those observed with risperidone preparations with immediate release.

The absolute oral bioavailability of paliperidone is 28%. Since absorption also depends on whether it is taken on an empty stomach or with a meal, it is necessary that patients decide on one type of ingestion and stick to it.

Paliperidone is most likely not extensively metabolised in the liver. In vivo , no indications of a significant metabolism of paliperidone by the enzyme forms CYP2D6 and CYP3A4 were found, although in vitro studies had suggested a possible involvement. The elimination of paliperidone is mainly through the kidneys, a reduction of the dose depending on renal function is required.

indication

The current indication is limited to the treatment of schizophrenia . Since the beginning of 2011 there has been an extension of the indication for the treatment of psychotic and manic symptoms of schizoaffective disorders (the first neuroleptic with this indication in the European Union). In December 2008, the previously submitted additional indication for the treatment of acute manic episodes in bipolar I disorders was withdrawn by the company because the clinical evidence was insufficient.

Side effects

Very common (over 10%)

Common (1-10%)

  • Conduction disorders, prolonged QT time (cardiotoxicity)
  • slow heartbeat, fast heartbeat, prolongation of the heart's QT interval
  • Dyspepsia vomiting, nausea, constipation, diarrhea
  • pharyngo-laryngeal pain
  • Cough, runny nose
  • Abdominal pain, abdominal discomfort
  • Toothache
  • Dry mouth
  • blurred vision
  • Dystonia, dizziness, dyskinesia, tremor
  • Mania, restlessness, anxiety, depression
  • Weight gain, weight loss, increased or decreased appetite
  • Bronchitis, upper respiratory tract infection, sinusitis , urinary tract infection, influenza

In September 2013, the manufacturer (Janssen-Cilag) pointed out the risk of intraoperative floppy iris syndrome (IFIS) in connection with treatment with risperidone or paliperidone in patients undergoing cataract surgery (cataracts ) in a Rote-Hand letter down.

Warnings

On April 9, 2014, numerous media reported that 17 schizophrenia patients in Japan had died after doctors injected them with the drug paliperidone. A causal relationship is unclear and the drug has neither been taken off the market, nor was it generally advised against taking it. There is (as of April 9, 2014) no warning from the German or European approval authorities. Spiegel Online says: “ Janssen Pharmaceuticals instructed doctors in Japan to use the drug with great care and to watch out for possible side effects, especially in combination with other antipsychotic agents. The substance remains in the body for at least four months after the injection. Some of the patients only died around 40 days after administration. In Japan, it has been given as an injection since November 2013. Since then, almost 11,000 people have been treated there. "

Isomerism and chemical properties

Paliperidone is chiral and is commercially available as a racemate (±) -paliperidone. It belongs to the group of benzisoxazole derivatives . Paliperidone is hardly soluble in 0.1 N hydrochloric acid and dichloromethane ; practically insoluble in water, 0.1 N sodium hydroxide and n -hexane; as well as slightly soluble in N , N -dimethylformamide .

Approval and Marketing

Paliperidone (in oral form: Invega ) has been approved throughout the EU ( central approval ) since June 2007 and in Switzerland since May 2008. In contrast to Germany and Switzerland, paliperidone is not on the market in Austria because the main association of Austrian social insurance institutions has refused to accept reimbursement. In 2007, the reason was initially a lack of a small pack, which is mandatory in Austria. After an additional 14-piece pack had been approved, the application was resubmitted in 2008 and finally rejected in early 2009.

On March 9, 2011 Janssen-Cilag announced that the depot form (paliperidone palmitate, trade name Xeplion ) had received approval from the European Commission. Dose strengths are 25, 50, 75, 100 and 150 mg.

Trevicta came onto the market in 2016 . As with Xeplion, this is also a paliperidone palmitate (sustained release preparation). However, this is administered in higher (active ingredient) doses and with different syringes than Xeplion and is designed to be effective for three months instead of just one month.

See also

literature

Individual evidence

  1. ↑ a b c data sheet Paliperidone from Sigma-Aldrich , accessed on April 16, 2011 ( PDF ).
  2. ^ EMA: Summary for the public .
  3. ↑ Ulrich Schwabe: Patent-protected analog preparations (Me-too list 2017 in the modified version from 2011)
  4. ↑ Isabel Hach: The active ingredient Paliperidon Certified training apotheke + marketing 2008 PDF ( Memento of the original from December 8, 2015 in the Internet Archive ) Info: The archive link has been inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. . @1@ 2Template: Webachiv / IABot / www.springer-gup.de
  5. ↑ Janssen-Cilag: Withdrawal Letter (English) (PDF; 27 kB) .
  6. ↑ Rote-Hand-Brief from Janssen-Cilag on September 9, 2013. (PDF; 397 kB) Accessed on September 10, 2013 .
  7. ^ Spiegel Online: Paliperidone: 17 dead after injection of schizophrenia drug , accessed on April 9, 2014.
  8. ↑ Janssen Pharmaceutica, press release: European Commission grants approval for XEPLION (R) for the treatment of schizophrenia .