Trospium

Trospium
Names
Trade namesRegurin, Sanctura, others[1]
IUPAC name
  • 3‑(2‑Hydroxy-2,2‑diphenylacetoxy)spiro[bicyclo[3.2.1]octane-8,1'‑pyrrolidin]-1'‑ium chloride
Clinical data
Drug classAntimuscarinic agent[2]
Main usesOveractive bladder[3]
Side effectsDry mouth, abdominal pain, constipation[3][4]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • C
Routes of
use		By mouth (tablets, capsules)
Onset of actionWithin 7 days[5]
Typical dose20 mg BID[3]
External links
AHFS/Drugs.comMonograph
Legal
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
Protein binding50–85%
Elimination half-life20 hours
Chemical and physical data
FormulaC25H30ClNO3
Molar mass427.97 g·mol−1
3D model (JSmol)
SMILES
  • OC(c1ccccc1)(c2ccccc2)C(=O)O[C@@H]3C[C@@H]5CC[C@H](C3)[N+]45CCCC4
InChI
  • InChI=1S/C25H30NO3/c27-24(25(28,19-9-3-1-4-10-19)20-11-5-2-6-12-20)29-23-17-21-13-14-22(18-23)26(21)15-7-8-16-26/h1-6,9-12,21-23,28H,7-8,13-18H2/q+1/t21-,22+,23+ checkY
  • Key:OYYDSUSKLWTMMQ-JKHIJQBDSA-N checkY

Trospium, sold under the brand name Sanctura among others, is a medication used to treat symptoms of overactive bladder.[3] It is taken by mouth.[3] Effects begin within 7 days.[5]

Common side effects include dry mouth, abdominal pain, and constipation.[3][4] Other side effects may include urinary retention, agitation, and anaphylaxis.[3][4] Safety in pregnancy is unclear.[6] It is a antimuscarinic agent with minimal effects on the central nervous system.[2] It works by causing the smooth muscle in the bladder to relax.[7]

Trospium was patented in 1966 and approved for medical use in 1974.[8] It is available as a generic medication.[4] In the United Kingdom a month of medication costs the NHS about £6 in 2021.[4] In the United States this amount costs about 30 USD.[9]

Medical uses

Trospium is used for the treatment of overactive bladder with symptoms of urge incontinence and frequent urination.[7][2][10]

It shouldn't be used with people who retain urine, who have severe digestive conditions, myasthenia gravis, narrow-angle glaucoma, or tachyarrhythmia.[7]

It should be used in caution with people who have problems with their autonomous nervous system (dysautonomia) or who have gastroesophageal reflux disease, or in whom fast heart rates are undesirable, such as people with hyperthyroidism, coronary artery disease and congestive heart failure.[7]

Trospium chloride is rated Pregnancy Category C,[10] as there are no adequate and well-controlled studies of trospium chloride in pregnant women and there were signs of harm to the fetus in animal studies. The drug was excreted somewhat in the milk of nursing mothers.[7] The drug was studied in children.[7]

Dosage

The typical dose is 20 mg two times per day.[3]

Side effects

Side effects are typical of gastrointestinal effects of anticholinergic drugs, and include dry mouth, indigestion, and constipation. These side effects lead to problems with adherence, especially for older people.[2] The only CNS side effect is headache, which was very rare. Tachycardia is a rare side effect.[7]

Mechanism of action

Trospium chloride is a muscarinic antagonist. Trospium chloride blocks the effect of acetylcholine on muscarinic receptors organs that are responsive to the compounds, including the bladder.[7] Its parasympatholytic action relaxes the smooth muscle in the bladder.[2] Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.[7]

Pharmacokinetics

After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4.0 to 16.1%). Peak plasma concentrations (Cmax) occur between 5 and 6 hours post-dose. Mean Cmax increases greater than dose-proportionally; a 3-fold and 4-fold increase in Cmax was observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. Trospium chloride exhibits diurnal variability in exposure with a decrease in Cmax and AUC of up to 59% and 33%, respectively, for evening relative to morning doses.[11]

Administration with a high fat meal resulted in reduced absorption, with AUC and Cmax values 70 to 80% lower than those obtained when trospium chloride was administered while fasting. Therefore, it is recommended that trospium chloride should be taken at least one hour prior to meals or on an empty stomach.[11]

Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5 to 50 ng/mL) were incubated with human serum in vitro. The 3H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma. The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters.[11]

The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 is not expected to contribute significantly to the elimination of trospium. Data taken from in vitro human liver microsomes investigating the inhibitory effect of trospium on seven cytochrome P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations.[11]

The plasma half-life for trospium chloride following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium. The mean renal clearance for trospium (29 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated.[11]

Chemical properties

Anticholinergic drugs used to treat overactive bladder were all amines as of 2003. Quaternary ammonium cations in general are more hydrophilic than other amines and don't cross membranes well, so they tend to be poorly absorbed from the digestive system, and to not cross the blood-brain barrier. Oxybutynin, tolterodine, darifenacin, and solifenacin are tertiary amines while trospium chloride and propantheline are quaternary amines.[12]

History

The synthesis of trospium was described by scientists from Dr. Robert Pfleger Chemische Fabrik GmbH, Heinz Bertholdt, Robert Pfleger, and Wolfram Schulz, in US. Pat. No. 3,480,626 (the US equivalent to DE119442), and its activity was first published in the literature in 1967.[13][14]

The first regulatory approval was granted in Germany in August 1999 to Madaus AG for Regurin 20 mg Tablets.[15]: 13  Madaus is considered the originator for regulatory filings worldwide.[16] The German filing was recognized throughout Europe under the Mutual Recognition Procedure.[15]: 13 

Madaus licensed the US rights to trospium chloride to Interneuron in 1999 and Interneuron ran clinical trials in the US to win FDA approval.[17][18] Interneuron changed its name to Indevus in 2002[19] Indevus entered into a partnership with Odyssey Pharmaceuticals, a subsidiary of Pliva, to market the drug in April 2004,[20] and won FDA approval for the drug, which it branded as Sanctura, in May 2004.[21][22] The approval earned Indevus a milestone payment of $120M from Pliva, which had already paid Indevus $30 million at signing; the market for overactive bladder therapies was estimated to be worth $1.1 billion in 2004.[23] In 2005 Pliva exited the relationship, selling its rights to Esprit Pharma,[24] and in September 2007 Allergan acquired Esprit, and negotiated a new agreement with Indevus under which Allergan would completely take over the US manufacturing, regulatory approvals, and marketing.[25] A month before, Indevus had received FDA approval for an extended release formulation that allowed once a day dosing, Sanctura XR.[26] Indevus had developed intellectual property around the extended release formulation which it licensed to Madaus for most of the world.[25]

In 2012 the FDS approved the first generic version of the extended release formulation, granting approval to the ANDA that Watson Pharmaceuticals had filed in 2009.[27] Annual sales in the US at that time were $67M.[28] European patents had expired in 2009.[29]

As of 2016, the drug is available worldwide under many brand names and formulations, including oral, extended release, suppositories, and injections.[1]

Society and culture

Marketing rights to the drug became subject to parallel import litigation in Europe in the case of Speciality European Pharma Ltd v Doncaster Pharmaceuticals Group Ltd / Madaus GmbH (Case No. A3/2014/0205) which was resolved in March 2015. Madaus had exclusively licensed the right to use the Regurin trademark to Speciality European Pharma Ltd. In 2009, when European patents expired on the drug, Doncaster Pharmaceuticals Group, a well known parallel importer, which had been selling the drug in the UK under another label, Ceris, which was used in France, began to put stickers on their packaging with the Regurin name. Speciality and Madaus sued and initially won based on the argument that 90% of prescriptions were already generic, but Doncaster appealed and won the appeal based on the argument that it could not charge a premium with a generic label. The case has broad implications for trade in the EU.[29][30]

Research

In 2007 Indevus partnered with Alkermes to develop and test an inhaled form of trospium chloride as a treatment for COPD; it was in Phase II trials at that time.[31]

References

  1. 1 2 Drugs.com international brands of trospium Archived 2019-10-22 at the Wayback Machine Page accessed May 13, 2016
  2. 1 2 3 4 5 Biastre K, Burnakis T (February 2009). "Trospium chloride treatment of overactive bladder". Ann Pharmacother. 43 (2): 283–95. doi:10.1345/aph.1L160. PMID 19193592. S2CID 20102756.
  3. 1 2 3 4 5 6 7 8 "Trospium Monograph for Professionals". Drugs.com. Archived from the original on 20 January 2021. Retrieved 20 September 2021.
  4. 1 2 3 4 5 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 824. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
  5. 1 2 Kreder, Karl; Dmochowski, Roger (10 July 2007). The Overactive Bladder: Evaluation and Management. CRC Press. p. 193. ISBN 978-0-203-93162-2. Archived from the original on 23 September 2021. Retrieved 20 September 2021.
  6. ↑ "Trospium Use During Pregnancy". Drugs.com. Archived from the original on 3 December 2020. Retrieved 20 September 2021.
  7. 1 2 3 4 5 6 7 8 9 "Regurin XL 60mg - Summary of Product Characteristics (SmPC) - (emc)". www.medicines.org.uk. Archived from the original on 17 January 2021. Retrieved 20 September 2021.
  8. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 446. ISBN 9783527607495. Archived from the original on 2020-11-15. Retrieved 2021-03-16.
  9. ↑ "Trospium Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 10 April 2021. Retrieved 20 September 2021.
  10. 1 2
  11. 1 2 3 4 5 Doroshyenko O, Jetter A, Odenthal KP, Fuhr U (2005). "Clinical pharmacokinetics of trospium chloride". Clin Pharmacokinet. 44 (7): 701–20. doi:10.2165/00003088-200544070-00003. PMID 15966754. S2CID 10968270.
  12. ↑ Pak RW, Petrou SP, Staskin DR (December 2003). "Trospium chloride : a quaternary amine with unique pharmacologic properties". Curr Urol Rep. 4 (6): 436–40. doi:10.1007/s11934-003-0023-1. PMID 14622495. S2CID 4512769.
  13. ↑ See US Patent 6,974,820 Archived 2017-10-27 at the Wayback Machine, Column 1 lines 31-34. which cites US 3,480,626 Archived 2021-08-29 at the Wayback Machine and Bertholdt H, Pfleger R, Schulz W (1967). "[On azoniaspire-compounds. 2. Preparation of esterified azoniaspire-compounds of nortropan-3-alpha- or 3-beta-ol (1)]". Arzneimittelforschung. 17 (6): 719–26. PMID 5632538.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ↑ DE patent 1194422, Bertholdt H, Pfleger R, Schulz W, "[Verfahren zur Herstellung von Azoniaspironortropanderivaten] (A process for preparing azonia-spirono-tropane derivatives)", issued 1965-06-10, assigned to Dr. Robert Pfleger Chemische Fabrik GmbH 
  15. 1 2 Medicines and Healthcare products Regulatory Agency. April 7, 2011 Public Assessment Report: Decentralised Procedure. Trospium Chloride 20mg Film-Coated Tablets UK/H/4220/001/DC UK licence no: PL 17507/0099 Auden Mckenzie Limited Archived 2016-10-09 at the Wayback Machine
  16. ↑ AdisInsight Trospium chloride Archived 2019-10-22 at the Wayback Machine Page accessed May 13, 2016
  17. ↑ Jeff Miller for the Boston Business Journal. Sep 23, 2002, Indevus to apply for new drug status for incontinence drug Archived 2016-10-09 at the Wayback Machine
  18. ↑ Matthew Herper for Forbes. Sept 25, 2002 A Biotech Phoenix Could Be Rising Archived 2016-10-09 at the Wayback Machine
  19. ↑ Indevus Press Release Archived 2017-03-01 at the Wayback Machine April 2, 2002
  20. ↑ Indevus Press Release. April 07, 2004 Indevus and PLIVA Sign Co-Promotion and Licensing Agreement for SANCTURA -Trospium Chloride Archived 2021-08-27 at the Wayback Machine
  21. ↑ CenterWatch. Sanctura (trospium chloride) Archived 2019-08-05 at the Wayback Machine Page accessed May 13, 2016
  22. ↑ Indevus Press Release. May 28, 2004 Indevus Announces FDA Approval Of Sanctura Archived 2016-08-20 at the Wayback Machine
  23. ↑ Neil Osterweil for First Word Pharma. May 28, 2004 FDA approves Indevus' Sanctura Archived 2016-10-09 at the Wayback Machine
  24. ↑ Urology Times. July 21, 2005 Novartis, P&G enter agreement for OAB drug Archived 2016-10-09 at the Wayback Machine
  25. 1 2 Indevus Press Release. Sept 19, 2007. Indevus Announces Allergan as New Partner for Sanctura Brand Archived 2016-08-20 at the Wayback Machine
  26. ↑ The Pharma Letter. August 13, 2007 Indevus' Sanctura XR approved by US FDA Archived 2016-10-09 at the Wayback Machine
  27. ↑ FDA ANDA 091289 approval letter Archived 2021-03-31 at the Wayback Machine October 12, 2012
  28. ↑ Watson Press Release. October 12, 2012 Watson's Generic Sanctura XR Receives FDA Approval Archived 2016-10-09 at the Wayback Machine
  29. 1 2 Lexology. March 6, 2015 Court takes a permissive approach to parallel importers within the EU Archived 2018-08-22 at the Wayback Machine
  30. ↑ R.P.C. (2015) 132 (7): 521-540. doi: 10.1093/rpc/rcv039
  31. ↑ UPI April 25, 2007 Alkermes, Indevus testing COPD drug Archived 2016-05-30 at the Wayback Machine
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