What are the pharmacokinetic strategies to raise ivermectin concentrations safely in humans?

1. Increase the dose or dosing frequency — proven feasible within limits

Human dose‑escalation trials demonstrate that ivermectin can be given at substantially higher doses than the standard 200 μg/kg with acceptable tolerability in healthy volunteers, with single doses up to 120 mg and repeat regimens tested without signals of severe CNS toxicity in that trial population ^[1]; pharmacokinetic modeling and trials for malaria transmission have explored regimens such as 600 μg/kg daily for three days or single 800 μg/kg doses to extend time above mosquitocidal thresholds ^{[2] [4]}, and population PK work shows largely linear PK over a range of doses ^[5].

2. Use formulation and vehicle engineering to change absorption and half‑life

Altering the pharmaceutical vehicle markedly changes ivermectin absorption, bioavailability and apparent half‑life — nonaqueous injectable or slow‑release vehicles produce prolonged absorption and much longer biological half‑lives in animal and formulation studies, demonstrating that sustained systemic exposure can be engineered by formulation choices ^{[6] [7] [8]}.

3. Targeted delivery to the site of action — inhaled or localized approaches

To raise tissue concentrations where needed while limiting systemic exposure, inhaled formulations have been proposed and tested preclinically: mouse studies of inhaled ivermectin show higher respiratory tract exposure and retention above in vitro antiviral concentrations for at least 24 hours, suggesting inhalation could increase lung levels without proportionally raising plasma concentrations ^[9], an idea echoed as a theoretical strategy in human PK analyses ^[10]. Human safety and formulation development would be required before clinical use ^{[10] [9]}.

4. Extend exposure via repeated dosing or long‑acting formulations for temporal coverage

Where the goal is to extend effective concentrations over days or weeks (for vector control or antiparasitic prophylaxis), PK modeling supports multi‑day regimens that increase time above targets compared with single doses — e.g., three days of 600 μg/kg extends time above a defined LC50 for mosquitoes from ~2 to ~7 days in simulations and trial designs ^[4]. Long‑acting injectable or depot formulations are a parallel strategy underpinned by formulation studies that demonstrate slow‑absorption profiles ^{[7] [6]}.

5. Pharmacokinetic modulation and drug–drug interactions — potential leverage, potential risk

Ivermectin is highly protein‑bound (~93%) and largely cleared via biliary routes and CYP3A4 metabolism; these features limit free plasma concentrations and create scope for interactions to modify exposure, but co‑administration with drugs affecting CYP3A4 could unpredictably raise total and unbound levels and increase toxicity risk ^{[3] [11]}. Trials co‑administering ivermectin with dihydroartemisinin‑piperaquine found no clinically meaningful PK interaction in that context but underlined the need for empirical evaluation of each combination ^[11].

6. Safety ceiling and realistic expectations — the limits set by PK and toxicology

Translating in vitro antiviral concentrations to humans is constrained by PK: antiviral in vitro concentrations reported for SARS‑CoV‑2 are orders of magnitude above plasma Cmax achieved even with very high oral doses, and modeling suggests achieving those concentrations orally would require doses far beyond approved ranges with uncertain safety ^{[3] [12]}. Thus, while dose escalation, formulation innovation, targeted inhalation, and controlled‑release products can raise local or systemic ivermectin concentrations, each approach must be validated against human safety data and realistic PK ceilings rather than in vitro targets alone ^{[3] [9]}.