El 12 de mayo de 2017 celebramos en la Fundación Ramó Areces una jornada con IS Global y Unitaid sobre enfermedades transmitidas por vectores, como la malaria, entre otras.

1. Bringing innovation to the front line: new tools to advance the
global response to vector-borne disease
Carlos Chaccour MD PhD
Ramón Areces fellow
Endectocides for malaria
elimination

2. Some relevant question
• How does it work?
• Where/when is it useful/testable?
• Does it add to the current paradigm?
• Is it safe?
• What evidence is needed for a policy
recommendation?

3. Outline
• Pharmacology
• Relevant evidence available
– Efficacy
– Safety
• Recent WHO assessment
• Key knowledge gaps

4. Summary
• Ivermectin kills mosquitoes who feed on treated
humans or animals
• Killing mosquitoes ≠ less transmission
• This is vector control, not transmission blocking
• Impact is on community – so would be delivered via
MDA (mass drug administration)
• Complementary tool for elimination
• Great safety profile at NTDs dosing (1-4 doses/year)
• Evidence on efficacy & safety needed for regulatory
and policy purposes

5. What is an endectocide

6. Mechanism of action
Omura et al. 2008

7. Pharmacokinetics
Elkassaby et al. 2008

8. The plasma concentration needed to kill 50% of
the biting Anopheles in a given time
A measure of efficacy similar
to the MIC50 and MIC90
used in microbiology
Lethal concentration 50 (LC50)

9. LC50 and time above lethality
Kobylinski et al. 2010

10. Ouedraogo et al. 2013
LC50 and time above lethality

11. Heterogeneity
LC95 LC75
LC50
LC25
Sub-lethal effects

12. Effect in the insectary

13. 0
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0.8
0.9
1
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time
Ivermectin Control
Chaccour et al. 2010
One day post 200 mcg/kg

14. Chaccour et al. 2010
14 days post 200 mcg/kg
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
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0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time
Ivermectin Control

15. Effect in the field

16. Alout et al. 2014

17. Alout et al. 2014

18. 29 relevant studies
(27 published)

19. Most relevant results
• Ivermectin reduces the survival of all
Anopheles species
• Anopheles species differ in their
susceptibility to the drug.

20. Most relevant results
• The effect is quick. Most of the lethal effect
is seen during the first three days after
feeding.
• The lethal effect of ivermectin is high.
Several studies report 9-day mortality
above 90% at doses or concentrations
often found in humans treated for
onchocerciasis.

21. Most relevant results
• The lethal effect has a dose-response
gradient
(lethal effect fades as drug levels drop)

22. Most relevant results: other effects
• Population age structure
• Vector fertility
• Vector behaviour

23. Most relevant results: Modelling
• Effect is dose-dependent with an
exponential relationship.
• Duration of mosquito-killing levels is a key
parameter.
• Ivermectin “buys” ACT-MDA rounds

24. Bellinger et al. 2016.

25. Bellinger et al. 2016.

26. Efficacy of
Ivermectin
Blood sources covered
Duration of
Plasma levels
Plasma
levels
reached

27. Additional (unexpected) effect
Inhibition of Plasmodium liver infection by ivermectin
Mendes et al. 2016

28. Safety

29. Summary
• Ivermectin is (remarkably) safe at current
dose for current indications
• Loa loa is an issue
• Limited data suggests higher cumulative
doses also safe
• Target coverage (efficacy) will inform the
need to include special populations

30. An extremely safe drug…
….With current use and
dose
• 200 mcg/kg 1-4 times a year
• More than 2.5 billion doses distributed in
MDA in 30 years
• More than 200 million treated every year

31. • Those with high Loa loa burden
(>30,000 mf/ml) are at risk of SAEs
including fatal encephalopathy
• Current strategies by the NTD
program include avoidance of highly endemic
areas and assurance of means to handle adverse
reactions in the localities where risk benefit warrants
treatment (do not treat with steroids, IV lines, bag and
mask devices…)
• Geographic overlap Loa loa – malaria
creates risk for new malaria indication
Loa loa

32. Is it safe at repeated or high doses?
Reference
Highest single
dose
Maximum
frequency
Maximum
number of doses
Maximum total
dose
Awadzi et al
1995 800 µg/kg Single Single
800 µg/kg
(once)
Awadzi et al
1999 800 µg/kg
Days
1 and 4
2
1.600 µg/kg (4
days)
Guzzo et al 2002 2.000 µg/kg
Days
1, 4 and 7
3
3.273 µg/kg
(one week)
Kamgno et al
2002
800 µg/kg 3-monthly 13
8.950 µg/kg (3
years)
Smit et al 2016 600 µg/kg Days 1, 2 and 3 3
1.800 µg/kg
(3 days)

33. Is it safe at repeated or high doses?
• Additionally, the drug is officially
recommended (CDC) for severe crusted
scabies
• Up to seven 200 mcg/kg in a month
• Australian label states “more than 3 doses
may be required”

34. Co-administration: antimalarials
• ACTIVE trial (+ Artemether-lumefantrine)
• IVERMAL (+ DHA-piperaquine)
• IMSEA (+DHA-pip + PQ)

35. WHO assessment
• Technical consultation:
“Ivermectin for malaria transmission control”
 Define the key missing data to make a policy
recommendation through
 Development of a target product profile (TPP) for
ivermectin as a tool to reduce malaria transmission.

36. WHO assessment
• Background document + draft TPP

37. WHO assessment
• Presented to MPAC
(September 2016)
• Feedback on TPP
• TPP as objective NOT
recommendation
• Review and re-submit

38. Key questions to be answered
• How to increase efficacy using existing
formulation?
• What is the role of metabolites?
• Define target dose, regimen, and coverage,
and expand safety database
• What is the safety at defined dose?
• What is the acceptability at define regimen?

39. carlos.chaccour@isglobal.org