Tafenoquine

{{Short description|Antimalarial drug}} {{Use dmy dates|date=November 2019}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 470476706 | drug_name = | INN = | type =  | image = Tafenoquine.svg | image_class = skin-invert-image | width = | alt = | caption =

| pronounce = ta fen' oh kwin | tradename = Krintafel, Arakoda, others | Drugs.com = {{drugs.com|monograph|tafenoquine-succinate-krintafel}} | MedlinePlus = a618050 | licence_CA =  | licence_EU =  | DailyMedID = Tafenoquine | licence_US =  | pregnancy_AU = C | pregnancy_AU_comment = <ref name="Drugs.com Pregnancy">{{drugs.com|pregnancy|tafenoquine}}</ref> | pregnancy_category= | routes_of_administration = By mouth | class = Antimalarial | ATCvet = | ATC_prefix = P01 | ATC_suffix = BA07 | ATC_supplemental =

| index2_label = as salt | CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 106635-80-7 | CAS_supplemental = | PubChem = 115358 | PubChemSubstance = | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB06608 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 103196 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 262P8GS9L9 | KEGG_Ref = {{keggcite|changed|kegg}} | KEGG = D10490 | KEGG2_Ref = {{keggcite|changed|kegg}} | KEGG2 = D10670 | ChEBI = 135752 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 298470 | NIAID_ChemDB = 006901 | PDB_ligand = | synonyms = Etaquine,<ref name="Peters1999">{{cite journal | vauthors = Peters W | title = The evolution of tafenoquine--antimalarial for a new millennium? | journal = Journal of the Royal Society of Medicine | volume = 92 | issue = 7 | pages = 345–352 | date = July 1999 | pmid = 10615272 | pmc = 1297286 | doi = 10.1177/014107689909200705 }}</ref> WR 238605,<ref name="Peters1999"/> SB-252263

| IUPAC_name = ''N''-[2,6-Dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine | C=24 | H=28 | F=3 | N=3 | O=3 | SMILES = FC(F)(F)c3cc(Oc1c(OC)cc(NC(C)CCCN)c2nc(OC)cc(c12)C)ccc3 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C24H28F3N3O3/c1-14-11-20(32-4)30-22-18(29-15(2)7-6-10-28)13-19(31-3)23(21(14)22)33-17-9-5-8-16(12-17)24(25,26)27/h5,8-9,11-13,15,29H,6-7,10,28H2,1-4H3 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = LBHLFPGPEGDCJG-UHFFFAOYSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Tafenoquine''', sold under the brand name '''Krintafel''' among others, is a medication used to prevent and to treat malaria.<ref name=Jul2019/> With respect to acute malaria, it is used together with other medications to prevent relapse by ''Plasmodium vivax''.<ref name=Jul2019>{{cite journal | vauthors = Haston JC, Hwang J, Tan KR | title = Guidance for Using Tafenoquine for Prevention and Antirelapse Therapy for Malaria - United States, 2019 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 68 | issue = 46 | pages = 1062–1068 | date = November 2019 | pmid = 31751320 | pmc = 6871897 | doi = 10.15585/mmwr.mm6846a4 }}</ref> It may be used to prevent all types of malaria.<ref name=Jul2019/> It is taken by mouth.<ref name=AHFS2019>{{cite web |title=Tafenoquine Succinate (Krintafel) Monograph for Professionals |url=https://www.drugs.com/monograph/tafenoquine-succinate-krintafel.html |website=Drugs.com |access-date=22 November 2019 }}</ref>

Common side effects include vomiting, headache, and dizziness.<ref name=AHFS2019/> Other side effects may include methemoglobinemia, trouble sleeping, and anaphylaxis.<ref name=AHFS2019/> In people with G6PD deficiency, red blood cell breakdown may occur.<ref name=AHFS2019/> Use in pregnancy is not recommended.<ref name=AHFS2019/> Tafenoquine is in the 8-aminoquinoline family of medications.<ref name=Jul2019/> The mechanism of action is unclear but it is effective both in the liver and bloodstream.<ref name=AHFS2019/><ref name=Jul2019/> A possible mechanism of action and other novel perspectives have been published.<ref>{{cite journal | vauthors = Markus MB | title = Safety and Efficacy of Tafenoquine for ''Plasmodium vivax'' Malaria Prophylaxis and Radical Cure: Overview and Perspectives | journal = Therapeutics and Clinical Risk Management | volume = 17 | pages = 989–999 | date = 2021 | pmid = 34526770 | pmc = 8435617 | doi = 10.2147/TCRM.S269336 | doi-access = free }}</ref>

Tafenoquine was approved for medical use in Australia and in the United States in 2018.<ref name=Jul2019/><ref name=Hou2019>{{cite journal | vauthors = Hounkpatin AB, Kreidenweiss A, Held J | title = Clinical utility of tafenoquine in the prevention of relapse of ''Plasmodium vivax'' malaria: a review on the mode of action and emerging trial data | journal = Infection and Drug Resistance | volume = 12 | pages = 553–570 | date = March 2019 | pmid = 30881061 | pmc = 6411314 | doi = 10.2147/IDR.S151031 | doi-access = free }}</ref> Tafenoquine is related to primaquine.<ref name=CDC2019Travel>{{cite web |title=Tafenoquine Approved for Malaria Prophylaxis and Treatment |url=https://wwwnc.cdc.gov/travel/news-announcements/tafenoquine-malaria-prophylaxis-and-treatment |website=Centers for Disease Control and Prevention (CDC) |date=25 April 2019 |access-date=22 November 2019}}</ref>

==Medical use== ===Prevention===

Tafenoquine may be used to prevent all types of malaria.<ref name=Jul2019/> For this use 200 mg 3 days before travel then 200 mg per week until one week after travel is recommended.<ref name=CDC2019Travel/>

===Treatment=== Tafenoquine is used for eliminating the hypnozoite stage of ''Plasmodium vivax'' and ''Plasmodium ovale'' that is responsible for relapse of these malarial infections, even when the blood stages are successfully cleared. Primaquine for 14 days can also be used for this. The advantage of tafenoquine is that it has a long half-life (2–3 weeks) and therefore a single treatment is sufficient.<ref name="pmid18541280">{{cite journal | vauthors = Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD | title = The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 102 | issue = 11 | pages = 1095–1101 | date = November 2008 | pmid = 18541280 | doi = 10.1016/j.trstmh.2008.04.024 }}</ref> For this use, a single dose of 300 mg is recommended.<ref name=CDC2019Travel/> It is used with another medication, such as chloroquine, that kills the parasites in the bloodstream.<ref>{{cite web |title=Conclusions and Recommendations from the Fifteenth Meeting of the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) |url=https://www.who.int/medicines/regulation/medicines-safety/publications/ACSoMP_15.pdf |website=WHO |access-date=22 November 2019}}</ref>

There is a need to determine whether or not tafenoquine kills the numerous, non-circulating asexual ''P. vivax'' parasites that are now known to occur in the spleen, bone marrow, and possibly elsewhere in chronic infections.<ref>{{cite journal | vauthors = Markus MB | title = Killing of Plasmodium vivax by Primaquine and Tafenoquine | journal = Trends in Parasitology | volume = 35 | issue = 11 | pages = 857–859 | date = November 2019 | pmid = 31522991 | doi = 10.1016/j.pt.2019.08.009 | s2cid = 202582476 }}</ref><ref>{{cite journal | vauthors = Markus MB | title = Putative Contribution of 8-Aminoquinolines to Preventing Recrudescence of Malaria | journal = Tropical Medicine and Infectious Disease | volume = 8 | issue = 5 | page = 278 | date = May 2023 | pmid = 37235326 | pmc = 10223033 | doi = 10.3390/tropicalmed8050278 | doi-access = free }}</ref>

== Chemistry == Tafenoquine contains a stereocenter and consists of two enantiomers. This is a mixture of (''R'')- and the (''S'')-forms: :{| class="wikitable" style="text-align:center" |- class="hintergrundfarbe6" ! colspan="2"| Enantiomers of tafenoquine |- | 250 px (''R'')-Form | 250 px (''S'')-Form |}

===Synthesis=== A chemical synthesis of tafenoquine has been reported:<ref>{{cite journal | vauthors=((Flick, A. C.)), ((Leverett, C. A.)), ((Ding, H. X.)), ((McInturff, E.)), ((Fink, S. J.)), ((Helal, C. J.)), ((DeForest, J. C.)), ((Morse, P. D.)), ((Mahapatra, S.)), ((O’Donnell, C. J.)) | journal=Journal of Medicinal Chemistry | title=Synthetic Approaches to New Drugs Approved during 2018 | volume=63 | issue=19 | pages=10652–10704 | date=8 October 2020 | url=https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00345 | doi=10.1021/acs.jmedchem.0c00345| url-access=subscription }}</ref> skin-invert-image|700px|center p-Anisidine [104-94-9] ('''1''') was heated in xylenes and ethyl acetoacetate to give 4'-methoxyacetoacetanilide [5437-98-9] ('''2'''). Cyclodehydration in the presence of acid led to 2-hydroxy-6-methoxy-4-methylquinoline [5342-23-4] ('''3'''). This was chlorinated with phosphorus oxychloride and sulfuryl chloride to give 2,5-dichloro-6-methoxy-4-methylquinoline [741233-61-4] ('''4'''). Methoxide addition, treatment with triethylphosphine in base, and subsequent nitration led to 5-chloro-2,6-dimethoxy-4-methyl-8-nitroquinoline [189746-21-2] ('''5'''). Ether formation between this highly activated quinoline and 3-(trifluoromethyl)phenol [98-17-9] ('''6''') occurred under basic conditions. Next, treatment with Darco KB and hydrazine promoted nitro reduction gave 2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-amine [106635-86-3] ('''7'''). Alkylation with 4-iodo-1-phthalimido-pentane [63460-47-9] ('''8''') incorporated the sidechain to give [106635-87-4 ] ('''9'''). Wolff-Kishner reduction of the phthalimide to the primary amine completed the synthesis of tafenoquine ('''10''').

==History== Tafenoquine was approved for medical use in Australia and in the United States in 2018.<ref name=Jul2019/><ref name=Hou2019/> Tafenoquine was given an orphan drug designation and was granted breakthrough therapy status in 2013 in the United States.<ref>{{cite web | url=https://www.fda.gov/media/114270/download | format=PDF | archive-url=https://web.archive.org/web/20191123044059/https://www.fda.gov/media/114270/download | title=Krintafel (tafenoquine succinate tablets) FDA Advisory Committee Briefing Document | website=Food and Drug Administration | date=12 July 2018 | archive-date=23 November 2019 | url-status=dead | access-date=22 November 2019}}</ref><ref>{{cite web | title=Krintafel Orphan Drug Designation and Approval | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=385812 | archive-url=https://web.archive.org/web/20191123045030/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=385812 | archive-date=23 November 2019 | url-status=dead | access-date=22 November 2019}}</ref>

==Society and culture== One version is made by GlaxoSmithKline,<ref name=AHFS2019/> while another is made by 60 Degrees Pharmaceutical.<ref>{{cite journal | vauthors = Tan KR, Hwang J | title = Tafenoquine receives regulatory approval in USA for prophylaxis of malaria and radical cure of Plasmodium vivax | journal = Journal of Travel Medicine | volume = 25 | issue = 1 | date = January 2018 | pmid = 30137454 | doi = 10.1093/jtm/tay071 | doi-access = free | pmc = 10956546 }}</ref>

===Names=== Etaquine was a generic name proposed by WRAIR, and subsequently rejected by CDER.{{citation needed|date=November 2019}}

Trade names * Kozenis (Australia)<ref>{{cite press release |date = 21 September 2018 |title = Kozenis (tafenoquine) approved by the Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria |url = https://www.mmv.org/newsroom/press-releases/kozenis-tafenoquine-approved-australian-therapeutic-goods-administration |location = |publisher = Medicines for Malaria Venture |access-date = 15 October 2018}}</ref> * Kodatef (Australia)<ref>{{cite web |title=Kodatef |url=https://www.nps.org.au/medicine-finder/kodatef |website=NPS MedicineWise |date=17 May 2022 |language=en}}</ref> * Arakoda (USA),<ref>{{cite web | title=Drug Approval Package: Arakoda | website=U.S. Food and Drug Administration (FDA) | date=13 February 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210607Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20191123043148/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210607Orig1s000TOC.cfm | archive-date=23 November 2019 | url-status=dead | access-date=22 November 2019}}</ref> Krintafel (USA)<ref>{{cite web | title=Drug Approval Package: Krintafel (tafenoquine) | website=U.S. Food and Drug Administration (FDA) | date=24 August 2018 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210795Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20191123041317/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210795Orig1s000TOC.cfm | archive-date=23 November 2019 | url-status=dead | access-date=22 November 2019}}</ref><ref>{{cite web | title=Drug Trials Snapshots: Krintafel | website=U.S. Food and Drug Administration (FDA) | date=6 August 2018 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-krintafel | archive-url=https://web.archive.org/web/20191123041626/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-krintafel | archive-date=23 November 2019 | url-status=live | access-date=22 November 2019}}</ref><ref>{{cite press release | date = 20 July 2018 | title = US FDA approves Krintafel (tafenoquine) for the radical cure of P. vivax malaria | url = https://www.mmv.org/newsroom/press-releases/us-fda-approves-krintafel-tafenoquine-radical-cure-p-vivax-malaria | publisher = Medicines for Malaria Venture | access-date = 15 October 2018}}</ref>

== References == {{reflist}}

== External links == * {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/tafenoquine | archive-url = https://web.archive.org/web/20200807204729/https://druginfo.nlm.nih.gov/drugportal/name/tafenoquine | url-status = dead | archive-date = 7 August 2020 | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Tafenoquine }}

Category:Antimalarial agents Category:Drugs developed by GSK plc Category:Orphan drugs Category:Phenol ethers Category:Quinolines Category:Trifluoromethyl compounds Category:Wikipedia medicine articles ready to translate Category:Diaryl ethers