How do single-dose versus repeated-dose ivermectin regimens change plasma Cmax and half-life?
Executive summary
Single oral doses of ivermectin produce a dose-proportional peak plasma concentration (Cmax) with a terminal half-life around 18–20 hours after typical human doses, while repeated or multi-day regimens usually produce only limited accumulation in plasma and do not dramatically raise Cmax or extend half‑life at commonly studied dosing schedules; however, higher or more frequent dosing regimens can raise overall exposure and the time a drug concentration remains above a target threshold [1] [2] [3] [4].
1. Single-dose pharmacokinetics: a predictable peak and an ~18–20 h half-life
Controlled human pharmacokinetic studies show ivermectin behaves largely linearly with dose for single administrations: Cmax and AUC scale with dose, time to peak (tmax) is roughly 3–4 hours, and the elimination half-life is on the order of a day (≈18–20 h) after single oral doses in healthy volunteers [1] [5] [2]. Those same human trials document substantial inter- and intra-individual variability in Cmax and AUC, and an apparent secondary rise in plasma levels 6–12 hours after dosing consistent with enterohepatic recycling [5] [2]. These single-dose parameters establish the baseline that all repeat‑dosing strategies are compared against.
2. Repeat dosing: little plasma accumulation at conventional schedules
Population pharmacokinetic modeling and clinical simulations indicate that common repeated regimens—weekly or three-times-weekly schedules at approved or modestly higher doses—produce very limited accumulation in plasma, so that overall plasma exposures (and thus Cmax) do not increase substantially compared with single-dose administration under those regimens [3]. The modeling work that compared a single 200 μg/kg dose to repeated dosing scenarios concluded that plasma ivermectin concentrations do not approach in vitro antiviral IC50s and that repeat dosing produced only modest increases in plasma exposure [3]. In other words, for many proposed repeat schedules, the drug’s half-life remains similar and steady‑state accumulation is minimal because the elimination phase clears much of the dose between administrations [3] [1].
3. Multi-day high-dose regimens: match single high Cmax or extend time-above-threshold
When dosing strategies change substantially—either by increasing daily dose or compressing dosing into multiple consecutive days—pharmacokinetic behavior can shift meaningfully. Modeling for malaria‑control strategies showed a 3‑day regimen (e.g., 600 µg/kg/day for 3 days) can produce a Cmax comparable to a single much higher bolus (e.g., 800 µg/kg) while importantly lengthening the time drug concentrations remain above a target lethal concentration for mosquitoes [4]. Similarly, dose-escalation studies demonstrate dose-proportional increases in Cmax and AUC with larger single doses, and higher total exposure with repeated higher-dose regimens in preclinical and controlled human studies [1] [6]. Thus, multi-day or high-dose repeats can increase systemic exposure even if standard low-frequency repeats do not.
4. Mechanisms and confounders: enterohepatic recycling, fed state, and variability
Published reports note enterohepatic recycling can produce a secondary plasma rise after single dosing, complicating simple peak/half‑life descriptions [2]. Food markedly increases ivermectin absorption (studies report ~2.5× higher AUC after a high‑fat meal), which alters Cmax without changing elimination kinetics per se and can affect comparisons between single and repeated dosing [7]. Large intersubject variability in absorption and disposition further clouds straightforward extrapolation from small studies to population outcomes [5]. These pharmacokinetic quirks mean repeat dosing effects depend on dose, interval, fed status, and subject factors.
5. What the evidence cannot yet fully resolve
Available human data and modeling consistently show limited plasma accumulation with conventional repeat schedules and an unchanged elimination half‑life in those contexts, while higher or more compressed dosing regimens can raise Cmax and overall exposure and prolong time above pharmacodynamic targets [3] [4] [1] [6]. However, direct, large-scale head‑to‑head human trials quantifying precise changes in terminal half-life after varied repeated regimens are limited in the literature provided; assertions about long-term accumulation or altered elimination kinetics beyond the studied schedules rely on modeling or preclinical data rather than extensive clinical trial evidence [3] [6].