What are the half-life and elimination pathways of ivermectin in humans?

1. Why the numbers disagree: different studies, different endpoints

Estimates of ivermectin’s “half-life” differ because authors report different measures: plasma half-life of the parent drug, terminal half-life after topical dosing, or half-life of metabolites. Clinical labels and many reviews place the parent plasma half-life at about 12–36 hours (FDA label ≈18 h; review ranges 12–36 h), while some PK studies and mass‑balance/metabolite analyses find mean terminal half-lives or metabolite half-lives that extend to multiple days or even weeks in extremes ^{[2] [1] [4] [3]}.

2. Most-cited, regulatory figure: ~18 hours but read the fine print

The U.S. Stromectol (ivermectin) prescribing information gives the commonly cited plasma half-life of approximately 18 hours after oral dosing and states that ivermectin and/or its metabolites are excreted almost exclusively in feces over an estimated 12 days, with under 1% recovered in urine ^{[2] [7]}. This is the figure used in clinical practice guidance, but it does not capture later‑appearing metabolites or tissue redistribution.

3. Metabolites and “post-ivermectin” effects: metabolites can outlast parent drug

Radio-labelled human studies and focused malaria/vector papers show metabolites peak later and persist longer than the parent compound; metabolite half-lives have been reported at ~55–72–around 72 h or higher, and some studies see ivermectin-related mosquitocidal activity long after parent drug is low in plasma—consistent with active or persistent metabolites ^{[8] [6] [3]}. A PLOS NTD trial even reported half-lives up to 81–91 h in certain cohorts for measured systemic exposure ^[4].

4. Principal elimination pathway: hepatic metabolism then fecal excretion

Ivermectin is primarily metabolized by CYP3A4 in gut and liver (human in vitro and in vivo work), and the drug and its metabolites are eliminated chiefly in feces; urinary excretion is minimal (<1%) ^{[5] [6] [2]}. Several sources underline enterohepatic recycling as a contributor to secondary plasma peaks and prolonged terminal phases ^{[9] [3]}.

5. Route and formulation matter: oral, topical, feeding status change kinetics

Absorption and apparent half-life vary with formulation and route. Oral absorption is rapid (Tmax ≈3–5 h; absorption half-life 0.5–2.5 h), and food (especially high‑fat meals) increases bioavailability markedly, which can change exposure and apparent elimination kinetics. Topical use yields lower systemic exposure but longer terminal half-lives in measured plasma (e.g., topical mean terminal half-life reported ~45 h, ranges up to 130 h) ^{[6] [10] [11]}.

6. Population and methodological differences widen reported ranges

Studies report larger half-life ranges (25–80 h; 12–66 h; 12–36 h) because subject factors (body fat, sex, disease state), assay sensitivity, sampling duration, and whether investigators measure parent compound or metabolites all influence the calculated half-life. The literature explicitly flags that kinetics (short plasma half-life) can be “disconnected” from prolonged pharmacodynamic effects (months of antiparasitic impact) ^{[12] [3] [4]}.

7. Practical takeaway for clinicians and policymakers

Use the regulatory label estimate (~18 h) as a baseline for dosing decisions, but recognize that metabolites and redistribution can prolong biologic and entomological effects for days to weeks; hepatic CYP3A4 interactions and high‑fat meals substantially affect exposure; and fecal excretion predominates (>99% of elimination pathway) ^{[2] [5] [6]}.

Limitations and where reporting is incomplete: available sources do not mention single definitive consensus on one half-life because investigators measure different analytes and cohorts; some newer papers report longer or shorter half-lives depending on methods ^{[3] [4]}.