Tiagabine

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Tiagabine
Tiagabine.svg
Tiagabine ball-and-stick model from xtal 2022.png
Clinical data
Pronunciation /taɪˈæɡəbiːn/
Trade names Gabitril
Other namesA-70569; A70569; CEP-6671; CEP6671; NO-050328; NO050328; NO-328; NO328
AHFS/Drugs.com Monograph
MedlinePlus a698014
Pregnancy
category
  • AU:B3
Routes of
administration 		Oral [1] [2] [3]
Drug class GABA reuptake inhibitor; GABA transporter 1 (GAT-1) inhibitor; Anticonvulsant; Hypnotic; Anxiolytic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 90% [1] [3] [5]
Protein binding 96% [1] [5]
Metabolism CYP3A4, possibly other CYP450 enzymes, glucuronidation [1] [5] [6]
Metabolites 5-Oxotiagabine, others [1] [3]
Onset of action ~1 hour (peak) [1]
Elimination half-life 4.5–9.0 hours [3] [7] [1]
Excretion Feces: 63% [1]
Urine: 25% [1]
Identifiers
  • (−)-(3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H25NO2S2
Molar mass 375.55 g·mol−1
3D model (JSmol)
  • O=C(O)[C@H]1CN(CCC1)CC/C=C(/c2sccc2C)c3sccc3C
  • InChI=1S/C20H25NO2S2/c1-14-7-11-24-18(14)17(19-15(2)8-12-25-19)6-4-10-21-9-3-5-16(13-21)20(22)23/h6-8,11-12,16H,3-5,9-10,13H2,1-2H3,(H,22,23)/t16-/m1/s1 Yes check.svgY
  • Key:PBJUNZJWGZTSKL-MRXNPFEDSA-N Yes check.svgY
   (verify)

Tiagabine, sold under the brand name Gabitril, is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. [2] [3] It is also used off-label in the treatment of anxiety disorders including panic disorder [8] and to treat insomnia. [9] [10] [11] The drug is taken orally. [2] [3]

Contents

Medical uses

Epilepsy

Tiagabine is approved by the United States Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures in epilepsy in individuals of age 12 and up. It is effective as monotherapy and combination therapy with other anticonvulsant drugs in the treatment of partial seizure. [12]

Other uses

Anxiety disorders

It may also be prescribed off-label by physicians to treat anxiety disorders, such as panic disorder and social anxiety disorder. [13] [14] [15] Tiagabine may be used alongside selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), or benzodiazepines for anxiety. [13]

Neuropathic pain

Tiagabine can be used in the treatment of neuropathic pain. [16] [17] [13] It can be used alongside antidepressants, gabapentin, other anticonvulsants, or opioids for neuropathic pain. [13]

Insomnia

Tiagabine has been used in the treatment of insomnia and has been found to enhance slow wave sleep (SWS) in this context. [9] [10] [11] However, the American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of tiagabine in the treatment of insomnia due to limited effectiveness and very low quality of evidence. [10]

Side effects

Side effects of tiagabine are dose-related. [12] The most common side effect of tiagabine is dizziness. [18] Other side effects that have been observed with a rate of statistical significance relative to placebo include asthenia, somnolence, nervousness, memory impairment, tremor, headache, diarrhea, and depression. [3] [18] [19] Adverse effects such as confusion, aphasia, stuttering, and paresthesia (a tingling sensation in the body's extremities, particularly the hands and fingers) may occur at higher dosages of the drug (e.g., over 8 mg/day). [18] Tiagabine may induce seizures in those without epilepsy, particularly if they are taking another drug which lowers the seizure threshold. [13] There may be an increased risk of psychosis with tiagabine treatment, although data is mixed and inconclusive. [5] [20] Tiagabine can also reportedly interfere with visual color perception. [5]

Overdose

Tiagabine overdose can produce neurological symptoms such as lethargy, single or multiple seizures, status epilepticus, coma, confusion, agitation, tremors, dizziness, dystonias, abnormal posturing, and hallucinations, as well as respiratory depression, tachycardia, and hypertension or hypotension. [21] Overdose may be fatal especially if the victim presents with severe respiratory depression or unresponsiveness. [21]

Pharmacology

Pharmacodynamics

Tiagabine increases the level of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, by blocking the GABA transporter 1 (GAT-1), and hence is classified as a GABA reuptake inhibitor (GRI). [7] [22]

Tiagabine is primarily used as an anticonvulsant in the treatment of epilepsy as a supplement. Although the exact mechanism by which tiagabine exerts its antiseizure effect is unknown, it is thought to be related to its ability to increase the activity of γ-aminobutyric acid (GABA), the central nervous system's major inhibitory neurotransmitter. Tiagabine is thought to block GABA reuptake into presynaptic neurons through inhibition of GAT-1 and, as a result of this action, allowing more GABA to be available for receptor binding on the surfaces of post-synaptic cells. [23] [24] In rat studies, tiagabine prolonged GABA-mediated inhibitory post-synaptic potentials in the hippocampus, as well as increased GABA concentration in the extracellular space of the globus pallidus, ventral palladum and substantia nigra. [1] However, tiagabine does not decrease neuronal GABA levels and induces compensatory GABA synthesis from glucose or glial glutamine precursors. [25]

Being a nipecotic acid derivative, introduction of 4,4-diphenylbut-3-enyl and 4,4-bis(3-methylthiophene-1-yl)but-3-enyl sidechain increased lipophilicity compared to the parent compound, allowing blood-brain barrier crossing and GAT-1 selectivity. [24]

Tiagabine also increases benzodiazepine-type anticonvulstants' affinity to cortical and limbic GABAA receptors and influences EEG measurements by increasing frontal activity and reducing posterior activity in the brain. [26] [27]

Tiagabine does not affect key cardiac ion channels. [28]

With regard to pharmacophore, the most stable binding mode of tiagabine in the GAT-1 transporter is that where the nipecotic acid fragment is located in the main ligand binding site, and aromatic thiophene rings are arranged within the allosteric site, which yields GAT-1 in an outward-open state. This interaction is mediated through GAT-1's sodium ion mimicry, hydrogen bonding and hydrophobic interactions. [29]

Pharmacokinetics

Absorption

Tiagabine is nearly completely absorbed (>95%) and has an oral bioavailability of 90%. [1] [3] The time to peak levels is approximately 1 hour. [3] Peak levels occur after 45 minutes in a fasted state and after 2.5 hours when taken with a high fat meal. [1] [3] A high fat meal decreases peak levels by 40% but does not affect area-under-the-curve levels. [1] [3] Tiagabine was administered with food in clinical trials and it is recommended that it be taken with food. [1] [3] The pharmacokinetics of tiagabine are linear over a dose range of 2 to 24 mg. [1] [3] Steady-state levels are achieved after 2 days of continuous dosing. [1]

Distribution

Tiagabine is widely distributed through the body. [3] Its volume of distribution is approximately 1 L/kg. [3] The drug readily crosses the blood–brain barrier. [3] The plasma protein binding of tiagabine is 96%, mainly to albumin and α1-acid glycoprotein. [1]

Metabolism

The metabolism of tiagabine has not been fully characterized. [1] In any case, it is metabolized by at least two known pathways. [1] One is thiophene ring oxidation resulting in 5-oxotiagabine and the other is glucuronidation. [1] 5-Oxotiagabine is said not to contribute to the pharmacodynamics of tiagabine. [1] In-vitro studies suggest that tiagabine is metabolized primarily by the cytochrome P450 enzyme CYP3A4, although involvement of other enzymes like CYP1A2, CYP2D6, or CYP2C19 has not been excluded. [1] Two other metabolites of tiagabine have yet to be identified. [3]

Elimination

Tiagabine is excreted about 2% unchanged. [1] [3] About 25% is excreted in urine and 63% is excreted in feces. [1] [3] The elimination half-life of tiagabine is 4.5 to 9.0 hours. [1] [3] The half-life of tiagabine was found to be decreased by 50 to 65% to 3.8 to 4.9 hours (range 2–5 hours) in patients whose hepatic enzymes had been induced with other anticonvulsants including carbamazepine, phenytoin, primidone, and phenobarbital. [1] [3] [30] In addition, the half-life of tiagabine is extended to 11.7 to 15.9 hours in hepatic dysfunction. [3] [30] These settings as such may require dose adjustment. [1] [3] [30]

Chemistry

Tiagabine is a GABA analogue and a derivative of nipecotic acid. [3]

History

Tiagabine was discovered at Novo Nordisk in Denmark in 1988 by a team of medicinal chemists and pharmacologists under the general direction of Claus Bræstrup. [31] The drug was co-developed with Abbott Laboratories, in a 40/60 cost sharing deal, with Abbott paying a premium for licensing the IP from the Danish company.[ citation needed ] It was approved for treatment of epilepsy in the United States in September 1997. [30]

US patents on tiagabine listed in the Orange Book expired in April 2016. [32]

Tiagabine was previously subject to Risk Evaluation and Mitigation Strategies (REMS) in the United States, which was instituted in 2010. [33] [34] However, this requirement was eliminated in 2012. [35]

Research

Other conditions

In addition to epilepsy, tiagabine was under formal development for the treatment of anxiety disorders, insomnia, and neuropathic pain. [33] However, development for all of these indications was discontinued. [33]

Bipolar disorder

There have been case reports and case series of tiagabine for treatment of bipolar disorder. [36] However, no clinical trials have been conducted. [36]

Effects on brain activity

Tiagabine (15 mg) enhances MEG delta power in healthy volunteers. MEG power change (averaged across all sources and epochs) induced by tiagabine (15 mg) in 14 healthy volunteers..png
Tiagabine (15 mg) enhances MEG delta power in healthy volunteers.

Tiagabine enhances the power of cortical delta (< 4 Hz) oscillations up to 1,000% relative to placebo, which may result in an EEG or MEG signature resembling non-rapid eye movement sleep even while the person who has taken tiagabine is awake and conscious. [37] This demonstrates that cortical delta activity and wakeful consciousness are not mutually exclusive, i.e., high amplitude delta oscillations are not always a reliable indicator of unconsciousness.

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 "Gabitril (tiagabine hydrochloride) prescribing information" (PDF). U.S. Food and Drug Administration.
  2. 1 2 3 Leach JP, Brodie MJ (January 1998). "Tiagabine". Lancet. 351 (9097): 203–207. doi:10.1016/S0140-6736(97)05035-6. PMID   9449883.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Adkins JC, Noble S (March 1998). "Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy". Drugs. 55 (3): 437–460. doi:10.2165/00003495-199855030-00013. PMID   9530548.
  4. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  5. 1 2 3 4 5 Leduc B (24 January 2012). "Antiseizure Drugs". In Lemke TL, Williams DA (eds.). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 562–. ISBN   978-1-60913-345-0.
  6. ↑ "Gabitril (tiagabine hydrochloride) Tablets. U.S. Full Prescribing Information" (PDF). Cephalon, Inc. Retrieved 8 April 2016.
  7. 1 2 Brodie MJ (1995). "Tiagabine pharmacology in profile". Epilepsia. 36 (Suppl 6): S7 –S9. doi:10.1111/j.1528-1157.1995.tb06015.x. PMID   8595791. S2CID   27336198.
  8. ↑ Schwartz TL, Nihalani N (October 2006). "Tiagabine in anxiety disorders". Expert Opin Pharmacother. 7 (14): 1977–1987. doi:10.1517/14656566.7.14.1977. PMID   17020423.
  9. 1 2 Walsh JK (April 2009). "Enhancement of slow wave sleep: implications for insomnia". J Clin Sleep Med. 5 (2 Suppl): S27 –S32. PMC   2824211 . PMID   19998872.
  10. 1 2 3 Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL (February 2017). "Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline". Journal of Clinical Sleep Medicine. 13 (2): 307–349. doi:10.5664/jcsm.6470. PMC   5263087 . PMID   27998379.
  11. 1 2 Abad VC, Guilleminault C (September 2018). "Insomnia in Elderly Patients: Recommendations for Pharmacological Management". Drugs Aging. 35 (9): 791–817. doi:10.1007/s40266-018-0569-8. PMID   30058034.
  12. 1 2 "Tiagabine", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID   31643697 , retrieved 2021-12-24
  13. 1 2 3 4 5 Stahl SM (2009). Stahl's essential psychopharmacology: the prescriber's guide; antipsychotics and mood stabilizers (3rd ed.). New York, NY: Cambridge University Press. pp. 523–526. ISBN   978-0-521-75900-7.
  14. ↑ Caldiroli A, Capuzzi E, Tagliabue I, Ledda L, Clerici M, Buoli M (February 2023). "New frontiers in the pharmacological treatment of social anxiety disorder in adults: an up-to-date comprehensive overview". Expert Opin Pharmacother. 24 (2): 207–219. doi:10.1080/14656566.2022.2159373. PMID   36519357.
  15. ↑ Dunlop BW, Papp L, Garlow SJ, Weiss PS, Knight BT, Ninan PT (June 2007). "Tiagabine for social anxiety disorder". Hum Psychopharmacol. 22 (4): 241–244. doi:10.1002/hup.846. PMID   17476705.
  16. ↑ Chandramouli J (2002). "Newer anticonvulsant drugs in neuropathic pain and bipolar disorder". J Pain Palliat Care Pharmacother. 16 (4): 19–37. doi:10.1080/j354v16n04_03. PMID   14635823.
  17. ↑ Backonja MM (September 2002). "Use of anticonvulsants for treatment of neuropathic pain". Neurology. 59 (5 Suppl 2): S14 –S17. doi:10.1212/wnl.59.5_suppl_2.s14. PMID   12221151.
  18. 1 2 3 Leppik IE (1995). "Tiagabine: the safety landscape". Epilepsia. 36 (Suppl 6): S10 –S13. doi:10.1111/j.1528-1157.1995.tb06009.x. PMID   8595787. S2CID   24203401.
  19. ↑ Eadie MJ, Vajda F (6 December 2012). Antiepileptic Drugs: Pharmacology and Therapeutics. Springer Science & Business Media. pp. 459–. ISBN   978-3-642-60072-2.
  20. ↑ Aronson JK, ed. (2009). "Antihistamines". Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 652–. ISBN   978-0-444-53266-4.
  21. 1 2 Spiller HA, Winter ML, Ryan M, Krenzelok EP, Anderson DL, Thompson M, et al. (2009). "Retrospective evaluation of tiagabine overdose". Clinical Toxicology. 43 (7): 855–859. doi:10.1080/15563650500357529. PMID   16440513. S2CID   25469390.
  22. ↑ Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, et al. (November 2005). "The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study". The Journal of Clinical Psychiatry. 66 (11): 1401–1408. doi:10.4088/JCP.v66n1109. PMID   16420077.
  23. ↑ "Gabitril (tiagabine) dosing, indications, interactions, adverse effects, and more". reference.medscape.com. Retrieved 2021-12-24.
  24. 1 2 Bhagat K, Singh JV, Pagare PP, Kumar N, Sharma A, Kaur G, et al. (February 2021). "Rational approaches for the design of various GABA modulators and their clinical progression". Molecular Diversity. 25 (1): 551–601. doi:10.1007/s11030-020-10068-4. PMC   8422677 . PMID   32170466.
  25. ↑ Patel AB, de Graaf RA, Rothman DL, Behar KL (July 2015). "Effects of γ-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ-Aminobutyric acid metabolism in the anesthetized rat In vivo". Journal of Neuroscience Research. 93 (7): 1101–1108. doi:10.1002/jnr.23548. PMC   4441585 . PMID   25663257.
  26. ↑ Frankle WG, Cho RY, Mason NS, Chen CM, Himes M, Walker C, et al. (2012). "[11C]flumazenil binding is increased in a dose-dependent manner with tiagabine-induced elevations in GABA levels". PLOS ONE. 7 (2) e32443. Bibcode:2012PLoSO...732443F. doi: 10.1371/journal.pone.0032443 . PMC   3288104 . PMID   22384252.
  27. ↑ Shaw AD, Chandler HL, Hamandi K, Muthukumaraswamy SD, Hammers A, Singh KD (September 2021). "Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions". European Neuropsychopharmacology. 50: 34–45. doi:10.1016/j.euroneuro.2021.04.005. PMC   8415204 . PMID   33957336.
  28. ↑ Kowalska M, Fijałkowski Ł, Kubacka M, Sałat K, Grześk G, Nowaczyk J, et al. (June 2021). "Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2". Molecules. 26 (12): 3522. doi: 10.3390/molecules26123522 . PMC   8226520 . PMID   34207748.
  29. ↑ Łątka K, Bajda M (November 2022). "Analysis of Different Binding Modes for Tiagabine within the GAT-1 Transporter". Biomolecules. 12 (11): 1663. doi: 10.3390/biom12111663 . PMC   9687605 . PMID   36359013.
  30. 1 2 3 4 Luer MS, Rhoney DH (November 1998). "Tiagabine: a novel antiepileptic drug". Ann Pharmacother. 32 (11): 1173–1180. doi:10.1345/aph.18053. PMID   9825084.
  31. ↑ Andersen KE, Braestrup C, Grønwald FC, Jørgensen AS, Nielsen EB, Sonnewald U, et al. (June 1993). "The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate". Journal of Medicinal Chemistry. 36 (12): 1716–1725. doi:10.1021/jm00064a005. PMID   8510100.
  32. ↑ "Search Results for Tiagabine". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration. Archived from the original on 22 April 2016. Retrieved 22 March 2016.
  33. 1 2 3 "Tiagabine". AdisInsight. 24 October 2021. Retrieved 24 October 2025.
  34. ↑ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/020646s017ltr.pdf
  35. ↑ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/020646s020ltr.pdf
  36. 1 2 Vasudev A, Macritchie K, Rao SN, Geddes J, Young AH (December 2011). "Tiagabine in the maintenance treatment of bipolar disorder". Cochrane Database Syst Rev. 2011 (12) CD005173. doi:10.1002/14651858.CD005173.pub3. PMC   12080104 . PMID   22161389.
  37. ↑ Frohlich J, Mediano PA, Bavato F, Gharabaghi A (June 2023). "Paradoxical pharmacological dissociations result from drugs that enhance delta oscillations but preserve consciousness". Communications Biology. 6 (1) 654. doi:10.1038/s42003-023-04988-8. PMC   10282051 . PMID   37340024.
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