Slow-release ivermectin formulations for malaria vector control

Current status and prospects

Carlos Chaccour MD MSc

Does IVM kill gambiae?

Direct feedings 24 hours after 200mcg/kgJID 2010

How much IVM kills gambiae?The minimum insecticidal concentration

22.4 ng/ml (18-27 ng/ml) Kobylinski 2010In vitro mixing + membrane

16 ng/ml (14-17 ng/ml) Kobylinski 2012In vitro mixing + membrane

6 ng/ml (4-7 ng/ml) Bousema 2013Volunteers + membrane

MIC + PK = The mosquitocidal window

22 ng/ml

18 hours

6 ng/ml

40 hours

Why is this important?A key factor for interrupting transmission

would be the time IVM remains in blood above mosquito-killing levels (i.e the width of the window)

(Slater et al 2014)

Widening the windowIncrease a single dose (mcg/kg)

i.e. Higher CmaxIntermitent treatment

i.e. Consecutive peaks

Slow release ----> Alter the curve (!)Oral (bowel transit time)Parenteral

First attempt…

Maeda 2003Cunnigham 2006

3 formulations: F – M - XI – II – III per subject

CuantificationsWeekly (12 weeks)Monthly (12-24 weeks)

Extensive toxicology study

1 2 3 4 6 7 8 9 10 11 12 16 20 240

102030405060708090

3F model

Weeks

IVM

levels

(n

g/m

l)

1 2 3 4 6 7 8 9 10 11 12 16 20 240

102030405060708090

3X model

Weeks

IVM

levels

(n

g/m

l)

Stable concentrations can be safely achieved modifying the formulation

Slow release technology available today

The modelled impact on transmission is very promising

Prospects, gaps and messageNew slow release formulations

Slow release pillTransdermal patchesPill + patch approachPegilated subcutaneous

Knowledge gaps

Joint work on TPP

Juliane Chaccour.Ángel Irigoyen, Ana G. Gil, Felix Hammann, Jose L Del Pozo.The MISSION Team: Santi, Chema, Rocio, Isa, Alberto.Campaign supporters and donnors