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For the final copy-edited version of this paper please follow this link to Trends In
Parasitology
DOI: http://dx.doi.org/10.1016/j.pt.2016.12.008
Oral, slow-release ivermectin: Biting back at malaria vectors.
Carlos J. Chaccour1,2,3
N. Regina Rabinovich1,4
1 ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de
Barcelona, Barcelona, Spain.
2 Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique.
3 Instituto de Salud Tropical Universidad de Navarra, Pamplona, Spain.
4 Harvard T.H. Chan School of Public Health, Boston, USA.
*Correspondence: carlos.chaccour@isglobal.org (C. J. Chaccour)
Keywords
Ivermectin, endectocide, slow-release, mass drug administration, malaria
elimination, vector control.
Abstract
Bellinger and colleagues offer an elegant twist for a promising new tool against
malaria. This formulation is designed to release ivermectin, a mosquito-killing drug
for 10 days after a single oral dose. This could reduce the vector population and
serve as a complementary tool for malaria elimination.
Endectocides: a new paradigm
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Vector control has been the cornerstone of the major gains against malaria in the last
15 years [1]. These gains are threatened by the emergence of insecticide resistance
and residual transmission. The latter is the transmission that persists in the absence
of significant insecticide resistance, after adequate deployment of long-lasting
insecticide-treated nets (LLINs) and/or indoor residual spraying (IRS) [2]. It is partly
the result of human behaviour (e.g. poor LLIN usage, IRS refusal), but also of
mosquitoes that feed on gaps left by these core vector control measures. These
gaps can either be temporal (crepuscular biting before people are under nets),
spatial (outdoor biting/resting) or even blood-source (feeding alternatively upon
animals or humans)[2].
Endectocides are systemic insecticides. These drugs are capable of killing
mosquitoes that feed on treated subjects regardless of the time and place of biting
[3, 4]. Endectocide mass drug administration could circumvent residual transmission
and potentially become a complementary tool for elimination.
The overall efficacy of an endectocide-based intervention would hinge upon three
main variables (a) the levels of the drug in the blood, as the mosquito-killing effect
can be directly related to these, (b) how long the drug remains in the blood above the
efficacy threshold and (c) the population coverage achieved, as mosquito exposure
will increase accordingly. Modelling confirms the importance of these variables [5, 6].
Ivermectin is possibly one of the drugs with the highest impact on global health ever
produced. It is effective against several neglected tropical diseases (NTDs) and is
distributed as a single dose in community campaigns to millions every year. It is also
a potent endectocide [4]. Over the past decade, it has in addition been
demonstrated to reduce Anopheles mosquito survival. It also reduces mosquito
fertility and flying capacity, affects sporogony [7] and even inhibits Plasmodium liver
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stages [8], virtually affecting all components of vectorial capacity. Its efficacy against
NTDs and excellent safety profile makes it a leading candidate for the endectocide
approach to malaria.
The half-life: a bump in the road
Ivermectin however has a relative short half-life. This means that the treatment
regime normally used for NTDs (a single oral dose of 150-200 mcg/kg) can only
sustain mosquito killing concentrations for 7 to 55 hours depending on vector
susceptibility. Several potential solutions have been proposed. The use of higher
doses can deliver a longer time above mosquito-killing concentrations but could
theoretically affect the risk-benefit equation, depending on peak levels reached.
Regimens with multiple lower doses avoid this risk but could be operationally
challenging. Parenteral slow-release formulations can sustain stable levels for weeks
to months [9] but require sterile techniques. Each solution has its own technical,
safety and logistical challenges.
An elegant solution
The delivery vehicle described in [5] is given orally and can offer weeks of effective
blood levels. It releases ivermectin in a controlled, near-linear rate, avoiding
unnecessary peaks, improving the efficacy/safety ratio and sparing active
pharmacological ingredient (API). Also, it can be administered on a single encounter
which reduces compliance and operational hurdles.
The formulation (Figure 1), tested in a pig model, has been carefully designed for
efficacy and safety. It is a capsule that contains a polymeric modular structure that
unfolds in the stomach into a star-shape configuration that delays passage through
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the pylorus while allowing the passage of food, even that with highest fibre content.
The ivermectin embedded in the biodegradable matrix remains stable under gastric
conditions and is gradually released for more than 10 days through the channels that
form as the matrix erodes. Stable mosquito-killing levels are sustained throughout
this period. Ivermectin, which is dosed in micrograms per kilo, is an appropriate drug
for this approach since large API quantities can be incorporated in a relative small
volume.
A modular design allows the incorporation of materials with different functions
(Figure 1). This includes a central piece that can sustain stress while folded yet
recoils quickly once out of the gelatine capsule and linkers that dissolve in a pH-
dependant way, causing the formulation to break apart rapidly in the intestinal
environment. No injury in to the gastric mucosa or obstruction was recorded after
administering 107 capsules in 35 occasions to 15 different pigs [5].
The modular design also allows for the incorporation of different drugs in the same
device. In the case of malaria, this could allow clearing the blood and hepatic stages
of the parasite, block transmission to mosquitoes by killing gametocytes, provide
prophylaxis for a long period and also reduce vectorial capacity by killing
mosquitoes, all with the same capsule given on a single encounter [10]. Combined
therapy for multiple diseases is also a possibility.
Finally, Bellinger and colleagues [5] used two malaria mathematical models to
assess the potential epidemiological impact of using this formulation in mass drug
administration (MDA) campaigns combined with dihydroartemisinin-piperaquine
(DP), an antimalarial with long prophylactic effect. In a seasonal setting with high
prevalence like southern Zambia and using operationally realistic MDA coverage of
60%, the mosquito-killing effect of long-lasting ivermectin results in a substantial
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increment in the probability of local malaria elimination. In a non-seasonal African
setting, DP MDA can significantly reduce prevalence. Adding long-lasting ivermectin
would greatly reduce the population coverage needed to achieve the same results,
i.e. 90% coverage with DP is similar to 60% coverage with DP + long-lasting
ivermectin.
The path forward
With long-lasting formulations, we must strive to find the balance between the impact
on transmission and the risk of selecting resistant mosquito-populations, the former
is driven by duration of mosquitocidal effect, while the latter is driven by prolonged
exposure. In this sense, the reduction of mosquito fitness and fertility seen even
after sub-lethal exposure to ivermectin offers some advantage.
Careful consideration should be given to development costs, the risk-benefit and the
potential for impact of this new approach beyond malaria including NTDs, endemic
ectoparasites and other vector-borne diseases.
Emerging data from a variety of trials with the existing ivermectin formulation will
provide the proof of concept for the molecule, which will add to the investment case
for novel formulations and endectocides in the long term.
References
1 Bhatt, S., et al. (2015) The effect of malaria control on Plasmodium falciparum in
Africa between 2000 and 2015. Nature 526, 207-211
2 Killeen, G.F. (2014) Characterizing, controlling and eliminating residual malaria
transmission. Malar J 13, 330
3 Chaccour, C.J., et al. (2013) Ivermectin to reduce malaria transmission: a research
agenda for a promising new tool for elimination. Malar J 12, 153
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4 Foy, B.D., et al. (2011) Endectocides for malaria control. Trends Parasitol 27, 423-
428
5 Bellinger, A.M., et al. (2016) Oral, ultra-long-lasting drug delivery: Application
toward malaria elimination goals. Sci Transl Med 8, 365ra157
6 Slater, H.C., et al. (2014) The potential impact of adding ivermectin to a mass
treatment intervention to reduce malaria transmission: a modelling study. J Infect Dis
210, 1972-1980
7 Kobylinski, K.C., et al. (2012) Ivermectin inhibits the sporogony of Plasmodium
falciparum in Anopheles gambiae. Malar J 11, 381
8 Mendes, A.M., et al. (2016) Inhibition of Plasmodium liver infection by ivermectin.
Antimicrobial agents and chemotherapy
9 Chaccour, C., et al. (2015) Screening for an ivermectin slow-release formulation
suitable for malaria vector control. Malar J 14, 102
10 The_malERA_Consultative_Group_on_Drugs (2011) A research agenda for
malaria eradication: drugs. PLoS Med 8, e1000402
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Figure legend
Figure 1. Schematic Representation of an Ivermectin Slow Release
Formulation with Prolonged Gastric Residence and its Components. Above: the
formulation is swallowed covered in a gelatine capsule. Once in the stomach, it
deploys in minutes into a stellate form that delays passage through the pylorus but
allows passage of food. pH-dependent linkers assure fracture of the structure under
minimal load once it reaches the intestine. Below: Size and shape (a) were optimized
to prolong gastric residence. The stellate configuration proved to be one of the most
appropriate to resist the gastric environment; it reduces stress while folded and
maximizes capsule occupation. The central recoil piece (b) was designed to sustain
strain in the capsule, recoil quickly and remain stable for several days. Resistance
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against folding proved to be one of the key parameters to avoid passage through the
pylorus. Ivermectin is released in an almost linear way from the biodegradable matrix
(c) through channels formed by material erosion. The drug remains stable in this
polymer for up to 14 days. Linkers that degrade quickly in intestinal environment (d)
were included to improve safety as the formulation would fracture in the event of
early passage through the pylorus. The modular structure also allows for the
incorporation of different drugs (with information from [5]).
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