What are the pharmacokinetics and brain penetration of ivermectin at toxic doses in humans?
Executive summary
Ivermectin is lipophilic, highly protein‑bound, and displays a human plasma half‑life around 18 hours with enterohepatic recycling and adipose accumulation that can prolong exposure [1] [2] [3]. The drug’s access to the central nervous system is normally restricted by P‑glycoprotein (P‑gp/ABCB1) and related efflux transporters, so even supratherapeutic oral doses in controlled studies produced limited clinical CNS toxicity, but impaired P‑gp function (genetic or drug‑drug interactions) or extreme overdose can allow brain penetration and GABA‑receptor–mediated neurotoxicity [3] [4] [5] [6] [7].
1. Pharmacokinetic primer: absorption, distribution, metabolism and elimination
After oral administration ivermectin is absorbed with Cmax and AUC influenced by food (higher AUC when given with high‑fat meals) and shows evidence of enterohepatic cycling with a secondary plasma rise at about 6–12 hours in some subjects; the reported plasma half‑life in humans is approximately 18 hours [2] [4] [1] [8]. Its lipophilicity drives a large volume of distribution and uptake into adipose tissue, producing prolonged terminal elimination and potential accumulation with repeated dosing [3] [8]. Metabolism is principally via CYP3A4 into multiple metabolites; interactions with CYP3A4 inhibitors or P‑gp inhibitors can increase systemic exposure and theoretically raise CNS exposure [5] [9].
2. Brain penetration at therapeutic and high doses: what the data say
Under normal human physiology the blood–brain barrier (BBB) limits ivermectin brain entry: P‑gp and other ABC transporters actively efflux ivermectin, so brain concentrations are low at therapeutic doses and distribution to the brain is "hindered" by the BBB [3] [5]. Controlled dose‑escalation in healthy volunteers found no objective evidence of CNS toxicity at doses up to ten times the highest FDA‑approved single dose (i.e., up to ~2,000 µg/kg in some arms), supporting limited brain penetration in people with intact BBB function [4] [10].
3. Mechanism of CNS toxicity when it occurs
The neurotoxic mechanism is well characterized: macrocyclic lactones like ivermectin act on ligand‑gated chloride channels including mammalian GABAA receptors when they reach relevant CNS concentrations, producing signs such as ataxia, mydriasis, emesis and sedation in susceptible animals and humans [7] [10]. Clinical reports and genetic studies show that loss or reduction of ABCB1 (MDR1/P‑gp) transport leads to higher brain concentrations and severe neurological effects in humans and animals, demonstrating that transporter failure—not a unique new mechanism—is the key to toxicity [6] [7] [11].
4. Toxic dosing, animal LD50s and limits of human data
Animal LD50s vary widely (e.g., mice ~25 mg/kg oral, dogs ~80 mg/kg) and some extrapolations produce broad human‑equivalent LD50 estimates, but these are not precise guides for human brain concentrations; human controlled trials show surprisingly high margins of safety but do not measure brain tissue levels directly [9] [4]. Pharmacokinetic and transporter knockout animal studies demonstrate dramatically higher brain accumulation and toxicity when P‑gp/BCRP function is absent, but human measurements of ivermectin in brain at toxic doses are scarce—case reports and genetic‑mutation analyses imply higher CNS exposure causes the observed severe events [12] [6] [11]. Therefore, direct quantitative human brain‑penetration data at overtly toxic doses are limited in the peer‑reviewed literature [12] [6].
5. Clinical modifiers and real‑world implications
Factors that can raise plasma or brain exposure include co‑administration of CYP3A4 or P‑gp inhibitors, high‑fat meals, obesity or malnutrition altering free drug fraction, repeated dosing or high single doses, and genetic ABCB1 loss‑of‑function variants; severe adverse neurologic events in people often coincide with impaired transporter function or with other causes of high exposure rather than routine therapeutic use [5] [4] [3] [6]. Special clinical contexts—such as high Loa loa microfilarial loads—produce post‑treatment neurological complications that are immunologic or parasitic in origin rather than classic ivermectin BBB penetration toxicity per se, complicating causal inference [10] [7].
6. Bottom line and gaps in evidence
Ivermectin’s pharmacokinetics produce prolonged systemic exposure and adipose accumulation, while the BBB—principally P‑gp—normally prevents brain levels from reaching GABAA‑agonist neurotoxic thresholds; high oral doses in trials produced minimal CNS effects, but transporter impairment or extreme overdose permits brain penetration and GABA‑mediated neurotoxicity as shown in animal models and human genetic cases [1] [4] [3] [6] [7]. Critical gaps remain in direct, quantitative measurements of ivermectin concentrations in human brain tissue at toxic doses, so mechanistic conclusions rely on transporter biology, animal knockout models, clinical pharmacokinetics and case reports rather than large human brain‑PK datasets [12] [6].