Tafenoquine is a long-acting 8-aminoquinoline antimalarial drug that is used for the radical cure of P. vivax malaria and prophylaxis of malaria. It has a longer half-life than primaquine of 14-19 days, allowing for single dose administration. Tafenoquine received its first global approval in 2018 for the radical cure of P. vivax malaria in patients aged 16 or older. It was also approved for malaria prophylaxis in patients aged 18 or older. Tafenoquine is contraindicated in patients with G6PD deficiency due to risk of hemolysis and all patients must be tested for G6PD deficiency prior to use.

1. Tafenoquine – Drug
review
Presenter-
Dr Nikita Ingale,
JR2
Pharmacology GMCH Nagpur
Guide-
Dr Vijay Motghare
Professor and Head
Pharmacology, GMCH Nagpur

2. …Anti-Malarials…
Tafenoquine
Malaria, caused by 4 species of the protozoal parasite Plasmodium, is endemic in most parts of India and other tropical
countries
The aims of using drugs in relation to malarial infection are:
• To prevent clinical attack of malaria (prophylactic).
• To treat clinical attack of malaria (clinical curative).
• To completely eradicate the parasite from the patient's body (radical curative).
• To cutdown human-to-mosquito transmission (gametocidal).

3. …Lifecycle…
Antimalarial therapy
1] Causal prophylaxis
2] Suppressive prophylaxis
3] Clinical cure
4] Radical cure
5] Gametocidal
Causal prophylaxis
[proerythrocytic schizon
Suppressive prophylaxi
[erythrocytic schizony]
Radical cure
[exoerythrocytic schizon
hypnozoites]
Gametocidal
[prevent transmission]
Clinical cure
[Terminate attack]

4. …Anti-Malarials…
1]Causal
prophylaxis
1]suppressive
prophylaxis
2]clinical cure
1]Radical
cure 1]Gametocidal
Atovaquone
Plus
Proguanil
+ +12
Tafenoquine belongs to class of 8- aminoquinolines

5. … Tafenoquine …
Tafenoquine
- Tafenoquine (Krintafel, Arakoda), is an orally-active 8-aminoquinoline
anti-malarial drug
- It is a long-acting analogue of primaquine
- Tafenoquine has been developed by GlaxoSmithKline in collaboration
with Medicines for Malaria Venture (MMV) as a radical cure for P. vivax
malaria and prophylaxis of malaria
- Tafenoquine has a long plasma t1⁄2 of 14-19 days Thus, it continues to
act for weeks after a single dose.

6. … Tafenoquine …
Tafenoquine
- Preclinical development of tafenoquine for babesiosis and pneumocystis
pneumonia has been discontinued
- Dose for radical cure  A single oral dose of tafenoquine 300 mg
has been approved in the USA for P. vivax malaria in patients aged ≥16
years who are receiving appropriate antimalarial therapy
- Dose for prophylaxis  tafenoquine 200 mg oral administered once
daily for 3 days (loading regimen) and thereafter once weekly
(maintenance/terminal prophylaxis regimen) has been approved in the
USA for the prevention of malaria (who are travelling to areas where
malaria is endemic)

7. “
Pharmacokinetics

8. … Pharmacokinetics…
Tafenoquine
- Absorption of tafenoquine is slow, with maximum plasma concentrations generally observed 12–15 h
after oral administration .
- Tafenoquine exhibits extensive protein binding (> 99.5%)
and has an apparent volume of distribution of ≈ 1600 L.
- The drug has an apparent clearance of ≈ 3 L/h and an average
terminal half-life of ≈ 15 days.

9. … Drug interactions…
Tafenoquine
- the pharmacokinetics of tafenoquine are not affected to a clinically relevant extent by
coadministration with chloroquine , dihydroartemisinin–piperaquine or artemether,
lumefantrine
- Likewise, tafenoquine do not have a clinically significant effect on the pharmacokinetics of
coadministered dihydroartemisinin, piperaquine, artemether or lumefantrine

10. “
Pharmacodynamics

11. …Mechanism of action…
Tafenoquine
- Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as
gametocytes of Plasmodium species that include P. vivax and Plasmodium falciparum
- The activity of tafenoquine against P. vivax hypnozoites prevents the development of blood-stage
parasites, which are responsible for relapses in P. vivax malaria
- This blood schizonticidal activity is slow and hence for the radical cure of P. vivax malaria,
tafenoquine has to be coadministered with other blood schizonticidal agents, such as chloroquine or
the artemisinin-based combination therapies (ACTs) dihydroartemisinin–piperaquine and artemether–
lumefantrine
PRIMAQUINE acts on
hypnozoites [tissue
schizogony] and gametes
TAFENOQUINE acts on
hypnozoites [tissue schizogony],
gametes and erythrocytic [ blood
schizogony]

12. …Mechanism of action…
tafenoquine interferes with mitochondrial function leading to the apoptotic-like death of the
organism
Tafenoquine induced mitochondrial dysfunction through the inhibition of cytochrome c
reductase (respiratory complex III)
decrease in the oxygen consumption rate and depolarization of mitochondrial membrane
potential.
reactive oxygen species generation, elevation of intracellular calcium levels and concomitant
nuclear DNA fragmentation
In addition, tafenoquine inhibits haematin polymerization (like chloroquine, but
unlike primaquine, which is inactive in this regard)
PRIMAQUINE TAFENOQUINE

13. … G6PD deficiency and Tafenoquine …
Tafenoquine
- All patients must be tested for G6PD deficiency prior to prescribing tafenoquine
- the drug is contraindicated in patients with G6PD deficiency or unknown G6PD status
- the haemolytic potential of single- dose tafenoquine 300 mg did not appear to be greater than that of a
14-day course of primaquine 15 mg/day
HAEMOLYTIC
POTENTIAL OF
PRIMAQUINE
HAEMOLYTIC
POTENTIAL OF
TAFENOQUINE

14. “
Adverse events

15. … Adverse events …
Tafenoquine
- Tafenoquine was generally well tolerated in clinical trials,
including the recommended dose of the drug for radical cure of P. vivax
and in recommended regimen of the drug for prophylaxis of malaria
- Most common observed side effects dizziness, nausea ,vomiting,
decreased haemoglobin and headache
- Therapeutic (300) and supratherapeutic (1200 mg) doses of tafenoquine
did not have a clinically meaningful effect on cardiac repolarisation
[ no QT prolongation ]
PRIMAQUINE side
effect profile
TAFENOQUINE side
effect profile

16. “
Tafenoquine vs Primaqui

17. which one???
Tafenoquine
Primaquine Tafenoquine
Differences
-Dose of 15 mg/day for 2 weeks
for radical cure
-t1⁄2 of 6- 8 hrs
-activity against erythrocytic phase – no
Similarities
-cautious use in G6PD deficient patients
-Side effects = nausea
Price
Price = 760/- for 10 tablets
Differences
-Dose - A single dose of tafenoquine 300 mg for
the radical cure
-t1⁄2 of 14-19 days
-activity against erythrocytic phase -- yes
Similarities
- cautious use in G6PD deficient patients
-Side effects = headache, dizziness, nausea
Price
Price = 350 dollars for 10 tablets

18. “
Current status

19. … Current status …
Tafenoquine
- Tafenoquine received its first global approval (in the USA) on the
20th of July 2018 for the radical cure (prevention of relapse) of P.
vivax malaria in patients aged 16 years
- Subsequently, tafenoquine received its second global approval (also
in the USA) on the 9th August 2018 for the prophylaxis of malaria
in patients aged ≥ 18 years.

20. … Current status …
Tafenoquine
- Tafenoquine received its first global approval (in the USA) on the
20th of July 2018 for the radical cure (prevention of relapse) of P.
vivax malaria in patients aged 16 years
- Subsequently, tafenoquine received its second global approval (also
in the USA) on the 9th August 2018 for the prophylaxis of malaria
in patients aged ≥ 18 years.
Primaquine
Tafenoquine

21. … Summary …
Tafenoquine

22. … References …
Tafenoquine
- James E. Frampton , Tafenoquine: First Global Approval, Drugs , Springer Nature Switzerland
AG 2018
- https://doi.org/10.1007/s40265-018-0979-2

23. … …
Tafenoquine
Next PG activity –
Drugs modulating
Potassium Channels
27/02/19
Dr Anisha

24. … …
Tafenoquine

25. “

27. How does drug resistance occur???
• reduced entry of antibiotic into pathogen
alteration of target proteins
enhanced export of antibiotic by efflux pumps
release of microbial enzymes that
alter or destroy the antibiotic
development of alternative pathways to those inhibited by the antibiotic