TAFENOQUINE
Name: Tafenoquine
Synonym: Etaquine, Krintafel,
Arakoda, WR238605
Chemical formula: C24H28F3N3O3
Molecular weight: 463.501
IUPAC name: N4-{2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl}pentane-1,4-diamine
SMILES:
COC1=CC(C)=C2C(OC3=CC=CC(=C3)C(F)(F)F)=C(OC)C=C(NC(C)CCCN)C2=N1
Indication: Tafenoquine is used for the
treatment and prevention of relapsed infection caused by Plasmodium vivax in patients of age 16 years and above.
Developmental stage: Phase III studies,
developing as a single-dose treatment.
Approved by US FDA July 2018 and by Australian TGA September
2018.
Approved in first malaria-endemic country (Brazil) in October
2019 and in Thailand in December 2019
Under review in 5 endemic countries (MMV, Medicines for
malaria venture).
Company: GlaxoSmithKline; MMV
About Plasmodium vivax malaria: Malaria caused by P. vivax have a significant impact on
the health and economy of the population of South-Asia, South-East Asia, Latin
America and Africa. P. vivax
infection is associated with relapses if not treated appropriately (National
guidelines for the prevention of malaria, South Africa, 2018). In P. vivax infection, some of the liver
stage schizonts become dormant, forming hypnozoites which may persist in the
liver from months to years. These dormant hypnozoites cause relapses when get reactivated
and release merozoites in the bloodstream, thus restarting the erythrocytic
stage. Clinical features of P. vivax
malaria include fever, chills, vomiting, malaise, headache and muscle pain. In
severe cases, it can be fatal. Drugs like mefloquine and atovaquone-proguanil
are effective against acute infections caused by P. vivax and used as prophylactic agents. But, with these relapses
can occur appropriately (National guidelines for the prevention of malaria,
South Africa, 2018). Chloroquine is recommended for treatment. For cases of
chloroquine-resistant P. vivax, ACTs or
the artemisinin-based combination therapies are the recommended treatment.
Description: Tafenoquine and primaquine
are currently the drugs of choice for vivax malaria. Tafenoquine is an
8-aminoquinoline analogue of primaquine which varies only on the presence of
5-phenoxy group (Rajapakse, 2015; Peters, 1999). It was first investigated by
the scientists at the Walter Reed Army Institute of Research (WRAIR) and
further developed collaboratively between GlaxoSmithKline and Medicines for
Malaria Venture (Ebstie, 2016). It was approved by FDA in 2018. It is used in
combination with other antimalarials for the prevention of relapse of P. vivax malaria and by itself as
prophylaxis against all species of malaria. It is not indicated to treat acute vivax malaria (Rajapakse, 2015).
Mechanism of action: The mechanism of action of
tafenoquine is unclear, but studies have indicated that tafenoquine is more
potent and less toxic than primaquine. The active 5,6 ortho quinone moiety of
tafenoquine seems to be related to its activity. It is thought to be redox
cycled by the parasite and upregulated in gametocytes and liver stages. Once
inside, the oxidated metabolite produces hydrogen peroxide and hydroxyl
radicals that lead to the parasite death (Drugbank; Ebstie, 2016).
On the other hand, tafenoquine inhibits heme polymerase in
blood stage of parasites which explains the activity against blood stages of
parasites (Drugbank; Ebstie, 2016).
Cautions: Tafenoquine is contraindicated in patients
with glucose-6-phosphate dehydrogenase (G6PD) deficiency and in patients who
are allergic to tafenoquine or similar 8-aminoquinoline medicines such as
primaquine. Also contraindicated in pregnancy, breastfeeding an infant with
G6PD deficiency or unknown G6PD status.
References:
Rajapakse, S., Rodrigo, C., Fernando, S.D. (2015) Tafenoquine
for preventing relapse in people with Plasmodium
vivax malaria. Cochrane Database Syst
Rev. Apr 29;(4):CD010458.
Peters, W. (1999) The evolution of tafenoquine--antimalarial
for a new millennium? J R Soc Med. 92(7), 345-352.
Ebstie, Y.A., Abay, S.M., Tadesse, W.T., Ejigu, D.A. (2016)
Tafenoquine and its potential in the treatment and relapse prevention of Plasmodium vivax malaria: the evidence
to date. Drug Des. Devel. Ther. 26(10), 2387-2399.
MMV, Medicines for malaria venture. Available from: https://www.mmv.org/related-story-type/tafenoquine?page=2
Drug bank. Available from: https://www.drugbank.ca/drugs/DB06608#reference-L3770
National
guidelines for the prevention of malaria, South Africa (2018). Department of
health, Republic of South Africa. Available from: https://www.nicd.ac.za/wp-content/uploads/2019/03/National-Guidelines-for-prevention-of-Malaria_updated-08012019-1.pdf
Tafenoquine
phase III studies. Available from: https://www.gsk.com/en-gb/media/press-releases/two-positive-phase-iii-studies-of-tafenoquine-for-the-radical-cure-of-plasmodium-vivax-malaria-published-in-the-new-england-journal-of-medicine/
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