Keep Factually independent
Whether you agree or disagree with our analysis, these conversations matter for democracy. We don't take money from political groups - even a $5 donation helps us keep it that way.
What are the pharmacokinetics of ivermectin after single versus multiple dosing in humans?
Executive summary
Single-dose ivermectin in humans shows dose-proportional plasma exposure with a plasma half-life around ~18 hours and most elimination in feces; single doses commonly used are 150–200 μg/kg but higher single doses (up to 800 μg/kg in trials) have been tested and modeled [1] [2] [3]. Multiple- or multi-day regimens (e.g., 3-day courses or repeated single doses) raise time-above-target concentrations and can extend mosquitocidal or antiparasitic effects despite only modest changes in Cmax when doses are spread over days—models predict a 3-day 600 μg/kg/day regimen can lengthen time above LC50 from ~2 days to ~6.8 days compared with some single-dose regimens [4] [3].
1. Single-dose basics: predictable exposure, short half-life, fecal elimination
Human pharmacokinetic studies and product labels report that ivermectin plasma concentrations are approximately proportional to dose and that the plasma half-life is about 18 hours; ivermectin and metabolites are eliminated almost exclusively in feces with <1% excreted in urine [1] [2] [5]. Single-dose regimens historically used for onchocerciasis and other parasitic infections are typically in the 150–200 μg/kg range, and single 12 mg or other fixed doses have been used in PK studies to characterize Tmax, Cmax and AUC [6] [1] [7].
2. Multiple dosing: goal is longer effect, not dramatically higher peak
Clinical and modeling reports emphasize that multiple-dose regimens are intended primarily to extend the duration that drug concentrations remain above a pharmacodynamic threshold (for example, mosquitocidal LC50), rather than to greatly increase peak concentration. Pharmacokinetic modeling suggests that spreading dose across three days (e.g., 600 μg/kg/day ×3) can achieve similar median Cmax to a single larger dose (e.g., single 800 μg/kg) while substantially increasing the median time above LC50 (from ~1.9 days to ~6.8 days in the cited model) [3] [4]. That dynamic underpins trials testing 3‑day and multi-day regimens for vector-control purposes [4].
3. Clinical trial comparisons: single vs multi-day regimens in field studies
A randomized open-label trial comparing a single 400 μg/kg dose to a three-day regimen (300 μg/kg/day) reported differences in mosquitocidal effect and pharmacokinetics; the single-dose arm showed superior longevity of effect at 10 days in that study, an unexpected finding that the authors note is unclear and warrants further investigation [8] [9]. This highlights that results can differ between modeled expectations and empirical outcomes in small trials with varied doses and endpoints [8] [9].
4. Dose linearity and variability: Cmax and AUC scale, but interindividual variability is high
Multiple human PK studies and phase I trials report linear increases in Cmax and AUC with dose (dose-proportional pharmacokinetics across a wide single-dose range), but also substantial inter- and intra-individual variability in exposure metrics (Cmax, AUC), influenced by weight and other factors [7] [10]. This variability is part of why both single high doses and multi-day regimens are being explored to ensure population-level efficacy for different uses [7] [3].
5. Pharmacodynamics outlasts plasma levels: a disconnect that matters clinically
Reviews note that ivermectin’s antiparasitic pharmacodynamics can persist longer than plasma PK would predict; elimination half-life is around a day, yet antiparasitic effects can last weeks to months after a single dose for some infections, indicating lingering tissue-level effects or pharmacodynamic mechanisms that extend beyond plasma exposure [6]. For vector control, the relevant PK/PD metric is time above a mosquito-lethal concentration (LC50), which is sensitive to both Cmax and the dosing schedule [4] [3].
6. Safety context and upper-dose experience
Investigators modeling high-dose regimens reference prior human tolerability data: single doses up to 800 μg/kg (and even reports of 2000 μg/kg in the literature cited for safety margin) have been used in studies to define margins, which supports testing of higher or multi-day regimens under trial conditions; nevertheless, safety data above commonly used doses remain limited and trials explicitly evaluate tolerability [3] [4]. The FDA label and product information recommend single doses in standard parasitic indications and note typical PK parameters [1] [2].
Limitations and competing viewpoints
- Available sources show consistent PK patterns (dose-proportionality, ~18 h half-life, fecal excretion) but differ about which regimen is optimal for vector control: modeling favors multi-day regimens to extend time above LC50 [3] [4], while at least one randomized trial found a single higher dose produced longer mosquitocidal effect than a 3-day schedule—an empirical contradiction that authors flagged as unexplained [8] [9].
- Sources report high interindividual variability, and field efficacy depends on coverage, dosing strategy, and transmission context, so PK alone cannot determine public-health impact [4] [7].
- Available sources do not mention long-term accumulation with standard intermittent annual MDAs for onchocerciasis beyond noting repeated annual use and that multi-dose short courses are being trialed [6] [2].
If you want, I can extract specific PK numbers (mean Cmax, AUC, Tmax, half-life by dose) from individual studies cited above and present them in a table with exact citations.