How do preclinical ivermectin dosing levels in mice compare with human pharmacokinetic tolerability in oncology studies?
Executive summary
Preclinical mouse studies of ivermectin report effective antitumor activity across a wide dose range—commonly 0.5–10 mg/kg and in some reviews up to 40 mg/kg—with many experiments using ~3–10 mg/kg to shrink tumors or sensitize chemotherapy in xenograft models [1] [2] [3] [4]. Human pharmacokinetic and tolerability data show that single doses up to ~2 mg/kg have been administered without serious adverse events and yield plasma concentrations reported in the low micromolar range (peaks around 1–5 μM depending on dose), but higher exposures have produced neurological toxicity in some human reports, leaving a narrow and uncertain translational window from effective mouse exposures to tolerable human concentrations [5] [6] [7].
1. Preclinical mouse dosing: numbers, variability, and reported efficacy
Mouse experiments testing ivermectin against tumors use a broad spectrum of regimens: some studies report tumor growth inhibition at doses as low as 0.5 mg/kg, while many xenograft and leukemia experiments used 3–10 mg/kg administered daily or intermittently to achieve tumor shrinkage or delay growth, and reviews note an even wider published range of 2.5–40 mg/kg with a typical median near 5 mg/kg [4] [1] [3] [2]. Preclinical work also documents that ivermectin can reduce tumor volumes by more than 50% in murine models and can synergize with conventional cytotoxics in vivo, but these antiproliferative concentrations in cell culture and some animal studies are often higher than exposures classically achieved in human antiparasitic dosing [8] [9] [4].
2. Human pharmacokinetics and tolerability reported in clinical pharmacology
Human pharmacokinetic studies and reviews show that standard antiparasitic dosing (100–200 μg/kg) produces plasma peaks on the order of tens of ng/mL (nanomolar scale), while escalated dosing in healthy volunteers up to ~2 mg/kg has been given without “serious” adverse reactions and yields systemic exposures reported in low micromolar units—examples include reported values up to ≈5.2 μM at 2 mg/kg in some datasets—though reported exposures vary with assay and metric used (Cmax vs AUC) [1] [6] [5] [10]. Safety reports note that high doses have produced severe neurological adverse events in some clinical contexts, and observational accounts of overdoses emphasize potential neurotoxicity, so tolerability at doses beyond those systematically tested remains a concern [7] [11].
3. Translational gap: plasma concentrations, tissue exposure, and pharmacodynamic relevance
Several preclinical anticancer effects are reported at concentrations in vitro in the micromolar range (IC50s around 1–5 μM for sensitive lines) and in vivo at mouse doses that produce serum concentrations in the low μg/mL range (e.g., 10 mg/kg oral gavage producing 2.1–2.7 μg/mL at 24 hours), which corresponds roughly to low micromolar concentrations depending on conversion and protein binding [10] [3] [6]. Comparatively, human studies that pushed dosing toward 2 mg/kg reached measurable micromolar exposures, suggesting some overlap between achievable human systemic concentrations and preclinical effective ranges—but the overlap is incomplete and complicated by species differences in distribution, protein binding, and tolerated chronic exposure [6] [3] [12].
4. Safety, limits, and why mouse doses don’t map neatly to human oncology use
Mouse median effective doses and tolerated regimens (often repeated daily dosing over days to weeks) do not translate directly into safe human oncology schedules because mice metabolize and distribute ivermectin differently, some preclinical antitumor doses approach or exceed the animal LD50 margins, and human escalations above antiparasitic doses have produced neurological toxicity in some reports [5] [7] [2]. Reviews and expert analyses therefore caution that while some preclinical models suggest “clinically feasible” concentrations, the translational gap remains large: robust clinical trials investigating dose, schedule, tumor penetration, and safety in cancer patients are absent or limited, and self-directed off-label use carries known risks [9] [11] [7].
5. Bottom line and recommended scientific posture
Preclinical mouse data demonstrate antitumor signals across doses frequently higher than standard human antiparasitic regimens, and selected human pharmacokinetic studies show that escalated dosing can, in some cases, reach overlapping micromolar plasma concentrations; however, tolerability constraints, reports of neurotoxicity at high exposure, species pharmacokinetic differences, and limited clinical evidence mean that efficacy in mice does not equate to an acceptable therapeutic window in humans without rigorous phase I/II oncology trials [1] [6] [7] [11]. Reporting and clinical decision-making should therefore emphasize this translational uncertainty and prioritize controlled clinical evaluation rather than extrapolation from variable mouse dosing regimens [9] [8].