Pharmacokinetics‐Pharmacodynamics of High‐Dose Ivermectin with Dihydroartemisinin‐Piperaquine on Mosquitocidal Activity and QT‐Prolongation (IVERMAL)

Abstract

High-dose ivermectin, co-administered for 3 days with dihydroartemisinin-piperaquine (DP), killed mosquitoes feeding on individuals for at least 28 days posttreatment in a recent trial (IVERMAL), whereas 7 days was predicted pretrial. The current study assessed the relationship between ivermectin blood concentrations and the observed mosquitocidal effects against Anopheles gambiae s.s. Three days of ivermectin 0, 300, or 600 mcg/kg/day plus DP was randomly assigned to 141 adults with uncomplicated malaria in Kenya. During 28 days of follow-up, 1,393 venous and 335 paired capillary plasma samples, 850 mosquito-cluster mortality rates, and 524 QTcF-intervals were collected. Using pharmacokinetic/pharmacodynamic (PK/PD) modeling, we show a consistent correlation between predicted ivermectin concentrations and observed mosquitocidal-effects throughout the 28-day study duration, without invoking an unidentified mosquitocidal metabolite or drug-drug interaction. Ivermectin had no effect on piperaquine's PKs or QTcF-prolongation. The PK/PD model can be used to design new treatment regimens with predicted mosquitocidal effect. This methodology could be used to evaluate effectiveness of other endectocides.

Ivermectin Dosing Strategy to Achieve Equivalent Exposure Coverage in Children and Adults

“…This study is the first to report pediatric ivermectin clearance based on collected concentration‐time data in children from Ivory Coast, with a clearance ranging from 1.1 to 25.1 (median 6.8, interquartile range 4.7–9.1) L/hour. In adults, we found a median apparent clearance value of 13.0 (range 4.0–19.8) L/hour, which is in agreement with previously reported values for apparent clearance in adults of 11.8 L/hour in white healthy volunteers (HVs) and 9.6 (6.5–14.6) L/hour for a typical adult of 60 kg in western Kenya with uncomplicated malaria . Based on reported exposure and dose, an apparent clearance of 6.8 L/hour in white male HVs and 17.4 L/hour in Hispanic male and female HVs can be derived, which are in agreement with our reported values as well.…”

“…Two population PK models have been published for ivermectin PK in adults, comprising a two‐compartmental model with first‐order absorption, which is in agreement with our developed population PK model for ivermectin in children and adults. Caution should be taken when comparing the results from these models directly, as in our study PK data were collected with DBS sampling, which results in approximately 17% lower concentrations than plasma measurements .…”

“…Ivermectin pharmacokinetics (PK) in adults has been described in a small number of healthy volunteers and patients with onchocerciasis, Trichuris trichiura infection, or malaria. [20][21][22][23][24][25] Recently, the PK of ivermectin has been studied in children, 26,27 and a different exposure was reported among age groups (e.g., preschool-aged children of 2-5 years of age, school-aged children of 6-12 years of age, and adults). Moreover, in children, several studies for treatment of strongyloidiasis have been performed with a lower dose than the standard single-dose administration of 200 μg/kg used in adults, namely 100 μg/kg, revealing only moderate cure rates.…”

“…The drug has been widely used off‐label in a single‐dose administration for various indications, and given that young children may have high prevalence of helminth infections and scabies and serve as an important reservoir of Plasmodium , there is a need to build an evidence base to determine safe and effective ivermectin doses in the pediatric population. Ivermectin pharmacokinetics (PK) in adults has been described in a small number of healthy volunteers and patients with onchocerciasis, Trichuris trichiura infection, or malaria . Recently, the PK of ivermectin has been studied in children, and a different exposure was reported among age groups (e.g., pre–school‐aged children of 2–5 years of age, school‐aged children of 6–12 years of age, and adults).…”

Ivermectin and COVID-19: A report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors' responses

“…However, this in vitro activity occurred at much higher concentrations (IC 50 ≈ 2-3 μM) than the very low (nanomolar) concentrations effective against many nematode species (Geary, 2005), obtained after a usual dose of 200 µg/kg. This micromolar concentration is also higher than the therapeutic peak plasma concentration (about 40 nM) measured in humans treated for onchocerciasis control with a standard dose of 150 μg/kg (Apud Shu et al 2000) and even after a high daily dose (600 μg/kg) where Cmax of 105-119 ng/ml (0.12-0.14 μM) has been obtained by PK/PD modeling (Smit et al, 2019).…”