Krintafel (Tafenoquine)
Jessica Ishimwe
Ingram School of Nursing, McGill University
NUR301: Pharmacology for Nursing 2
William Archambault and Jayalakshmi Caliaperumal
March 14, 2023
DRUGS TODAY
2018/07/24
FDA approves
new drug for
antimalarial
relapse
by Shakespeare
Staff Writer
Krintafel tablets (MedScape, n.d.)
On July 20th, the U.S. Food and Drug Administration
(FDA) approved Krintafel, an antimalarial drug, to the
market. This is a novel addition to the world of
pharmacology and medicine, as it is the first new drug
in its category in more than 60 years (Ratner, 2018).
Krintafel is a "long-acting synthetic analogue" of
primaquine (Ratner, 2018), an antimalarial drug which
has been on the market since 1952, according to the
National Academies of Sciences, Engineering, and
Medicine (2020). Like primaquine, Krintafel is a part of
the aminoquinoline class. Its molecular structure is the
same as primaquine, with two extra methoxy groups
and a 3-trifluoromethylphenoxy substitution in the
quinoline ring (see the picture on the next page)
(Ratner, 2018).
The news of its recent approval comes after several
years of clinical trials. In its first clinical trial, a doubleblind, controlled study was conducted with 522 adults
positive for P. vivax. These patients received
chloroquine and either a one-time dose of 300mg of
Krintafel, an active control or placebo. After 6 months,
patients were assessed
for malaria relapse. It was found that the risk of
recurrence was reduced by 76% with Krintafel and
chloroquine compared to placebo and chloroquine. A
second double-blind, controlled study was conducted
with 111 participants, where one group received
chloroquine and 300mg of Krintafel or chloroquine and
placebo. The group receiving Krintafel had a recurrencefree rate of 84% after 6 months, compared to the placebo
group's 39% (GSK, 2020).
Malaria is a global health problem most prominent in
Africa, and also occurring in Central and South America,
the Caribbean, Asia, Eastern Europe and the South Pacific
(CDC, 2022). This disease is caused by an infection with
parasites belonging to the Plasmodium genus (P.
falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi).
Malaria symptoms include high fever, chills, headache,
nausea, vomiting, body aches, anemia, jaundice, and
without treatment can lead to severe illness and death
(Menkin-Smith & Winders, 2022). It was responsible for
241 million cases and 627,000 deaths worldwide in 2020
(WHO, 2021).
Plasmodium falciparum and Plasmodium vivax are the
two parasites most associated with malaria infections.
P. falciparum accounts for more deaths while P. vivax
is more widespread, and therefore results in significant
numbers of cases and deaths. These parasites enter
humans' bloodstream in the form of sporozoites
following a bite from an infected mosquito. The
sporozoites then travel to the liver and enter
hepatocytes, where they form schizonts. These
eventually rupture and cause Plasmodium merozoites
to be released in the bloodstream, which cause the
malaria symptoms listed above. P. vivax and P. ovale
can release dormant hypnozoites, which can remain in
the liver for months to years and cause relapse. The
incubation period of malaria is 12 to 17 days, but
because of these hypnozoites, relapse can occur after
2 years (Menkin-Smith & Winders, 2022).
Krintafel is used to prevent relapse of P. vivax and P.
ovale infections. The mechanism of action of
tafenoquine (the active ingredient in Krintafel) is to act
against pre-erythrocytic forms of P. vivax and ovale
located in the liver as well as the parasite's asexual
erythrocytic forms and gametocyte versions (i.e. the
dormant forms of the parasites) (GSK, 2020). This
prevents its progression into the blood and therefore
stops the existing infection from developing into a
severe and fatal disease (Duffy et al., 2012). There is no
information yet on the molecular target of the drug
(GSK, 2020).
Due to its difference in structure from primaquine (the
additional methoxy groups and phenoxy group),
Krintafel can stay in the bloodstream longer. This
provides a huge benefit in treatment adherence, as
patients can complete treatment with one dose of the
drug compared to the usual and difficult 14-day
course of primaquine treatment (Ratner, 2018). Its halflife elimination is 15 to 16.5 days, the time to peak is 12
to 15 hours and its absorption is increased with food
(Lexicomp, 2023).
Adverse effects of the drug include: diarrhea,
methemoglobinemia (a condition of elevated
methemoglobin, where not enough oxygen is
delivered to blood cells (Prchal, 2022)), headaches,
back pain, epithelial keratopathy (a condition where a
line or a band forms across the cornea (Singh &
Tripathy, 2023)), motion sickness, nausea, vomiting,
decreased hemoglobin, increased serum alanine
aminotransferase and rare but serious hypersensitivity
reactions. Patients should be screened for G6PD
deficiency prior to treatment, as hemolytic anemia can
.
Chemical structures of primaquine and
tafenoquine (ResearchGate, n.d.)
occur in these cases. Psychiatric effects have been reported
and therefore a history of psychiatric illness should be
assessed before undergoing treatment, and psychiatric
symptoms should be monitored. Finally, Krintafel is
contraindicated in patients with hypersensitivity to
tafenoquine or other 8-aminoquinolines, like primaquine
(Lexicomp, 2023).
"This new drug approval means so much to me," shared
Jessica Ishimwe, a nursing student at McGill University. "My
pharmacology course encourages me to study drugs and stay
up to date with advances in medical/pharmacological
research and keep up with new, interesting drugs that are
hitting the market. Krintafel is a drug that piqued my interest
because of how much of an impact malaria has had on my life.
Being from Burundi, I am unfortunately very familiar with the
disease. Every time I visit home, there are several vaccines I
have to get beforehand, and once I get there, bug spray and
mosquito net canopies become a lifeline. I am lucky enough
to have never contracted the disease. However, over the years
I have seen friends and family members travel home and end
up hospitalized for weeks, fighting for their lives against
malaria. Sadly, my own dad was on a trip to Burundi to work
on antimalarial technologies among other entrepreneurial
efforts, when he died suddenly from a co-infection with
malaria and complications of Hepatitis B. The fight against
malaria and other diseases common in Africa is something
that will always be close to my heart, and any advances in this
sector is important."
Krintafel already seems like a drug that will be important in the
treatment of malaria and the decrease of its transmission
worldwide. It brings hope for the spur of more research and
advancements in its class.
Tagged: Malaria, Krintafel, Drug Discovery,
Pharmaceutical Science, Burundi
Word count: 971 Words.
References
Duffy, P. E., Sahu, T., Akue, A., Milman, N., Anderson, C. (2012). Pre-erythrocytic malaria vaccines:
identifying the targets. Expert Review of Vaccines, 11(10), 1261-1280.
https://doi.org/10.1586/erv.12.92
GlaxoSmithKline. (2020). Krintafel.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210795s001lbl.pdf
Lexicomp (2023). Tafenoquine: Drug information. UpToDate. Retrieved March 19, 2023, from
https://www.uptodate.com/contents/tafenoquine-drug-information
National Academies of Sciences, Engineering, and Medicine. (2020). Assessment of long-term health
effects of antimalarial drugs when used for prophylaxis. National Academies Press.
https://www.ncbi.nlm.nih.gov/books/NBK556600/
National Center for Emerging and Zoonotic Infectious Diseases. (2022, September 13). Malaria.
Center for Disease Control and Prevention. https://wwwnc.cdc.gov/travel/diseases/malaria
[Photograph of Chemical structures of primaquine and tafenoquine]. (n.d.).
https://www.researchgate.net/figure/Chemical-structures-of-primaquine-andtafenoquine_fig1_261732761
[Photograph of Krintafel tablets]. (n.d.). https://www.medscape.com/viewarticle/899667
Prchal, J. T. (2022). Methemoglobinemia. UpToDate. Retrieved April 5, 2023, from
https://www.uptodate.com/contents/methemoglobinemia
Ratner, M. (2018). FDA approves first single-dose antimalarial. Nature Biotechnology, 36(785).
https://doi.org/10.1038/nbt0918-785a
Singh, P., Tripathy, K. (2023). Keratopathy. StatPearls Publishing.
https://www.ncbi.nlm.nih.gov/books/NBK562153/
World Health Organization. (2021). World malaria report 2021.
https://www.who.int/publications/i/item/9789240040496