What are the pharmacokinetic thresholds for ivermectin neurotoxicity in humans and how do reported serum levels in veterinary‑product cases compare?
Executive summary
Ivermectin produces neurotoxicity in humans when it accumulates in the central nervous system — a process normally blocked by P‑glycoprotein — and clinical reports link toxicity to doses well above standard human regimens and to parenteral or veterinary formulations used improperly [1] [2] [3]. Published animal work defines a lower brain‑uptake threshold for ivermectin than for related drugs and shows dramatic brain accumulation when P‑gp is absent, but the human literature does not supply a clear, validated serum concentration “cutoff” for neurotoxicity; clinical series therefore use dose/exposure patterns as proxies [4] [5] [6].
1. What clinicians mean by a “pharmacokinetic threshold” for ivermectin neurotoxicity
Pharmacokinetic threshold here denotes the exposure at which ivermectin crosses the blood–brain barrier (BBB) in sufficient amounts to engage central GABA(A) and related chloride channels and produce neurologic signs; in humans the BBB is normally protected by P‑glycoprotein (P‑gp), so blood concentrations alone are an imperfect predictor of risk because brain penetration depends on efflux capacity as well as dose [1] [4].
2. Therapeutic dosing, expected safety margin, and how toxicity has been defined clinically
Recommended single‑dose therapy in humans for parasitic diseases is about 0.2 mg/kg, and standard oral formulations are designed with that safety margin in mind; most clinical and regulatory summaries describe minor neurological adverse events at therapeutic use but consider the drug “usually exceptionally safe” when dosed appropriately [4] [6] [7]. Toxicity cases during the COVID‑19 era clustered in older men who ingested doses above recommendations, often for days or as large single intakes, producing encephalopathy, ataxia, somnolence and more severe presentations [3] [8].
3. How animal and genetic models set biological plausibility for thresholds
Knockout and P‑gp‑deficient animal models show why thresholds vary: mice lacking MDR1/P‑gp accumulate ivermectin in brain at levels many‑fold higher than normals and develop neurotoxicity at much lower systemic doses, and comparative work shows ivermectin enters brain faster and has a lower brain‑uptake threshold for neurotoxicity than moxidectin [4] [5] [1]. These models demonstrate that a “safe” serum concentration in one individual could be dangerous in another with impaired P‑gp function or interacting drugs that inhibit efflux [1].
4. What the clinical case literature and poison‑center series actually report about exposures and measured levels
Published human case reports and poison‑center series emphasize ingested dose and route rather than standardized serum concentration thresholds: veterinary‑product cases commonly involve very large single doses or repeated high daily dosing and produce faster, more severe neurotoxicity than ordinary prescription tablets [3] [8]. A notable report describes a patient who received cumulative 155 mg (oral + intravenous veterinary product) over 4 days and developed severe neurotoxicity, and the authors conclude that oral dosing >0.4 mg/kg/day combined with IV veterinary bolus produced the event — but the paper documents exposure and clinical course rather than a numeric serum‑level cutoff [2].
5. Direct answer: pharmacokinetic thresholds in humans and where veterinary‑product cases sit relative to them
There is no robust, universally accepted human serum concentration threshold for ivermectin neurotoxicity reported in the available literature; instead, human risk is characterized by exposure patterns (doses >>0.2 mg/kg, repeat dosing, parenteral/veterinary routes) and by host factors that increase brain penetration such as P‑gp deficiency or interacting drugs [4] [1] [2]. Veterinary‑product cases almost uniformly represent exposures well beyond typical human therapeutic dosing and therefore sit on the hazardous side of inferred pharmacokinetic thresholds — they are functionally supra‑threshold events even when papers do not report a formal serum ng/mL “breakpoint” [3] [8] [9].
6. Caveats, alternative explanations and reporting gaps
Alternative viewpoints stress that ivermectin is very safe at intended doses and that serious neurologic events are rare in supervised use, while the literature also raises the possibility that co‑infections (e.g., Loa loa), genetic polymorphisms in MDR1, or drug interactions may explain some severe cases independent of total dose [6] [1]. Critical reporting gaps remain: human studies with paired plasma and CSF concentrations across a range of doses and genotypes are scarce, so clinicians must rely on observed dosing thresholds and mechanistic animal data rather than a validated human serum concentration to define toxicity risk [4] [5] [2].