How do formulation, route (oral vs topical), age, and liver function alter ivermectin accumulation with repeated doses?
Executive summary
Oral ivermectin produces substantially higher and dose‑proportional systemic exposure than topical formulations, but repeated dosing of standard oral regimens shows only modest accumulation in most human studies (AUC day7/day1 ≈1.24–1.40 for higher doses), while repeated topical 1% cream reaches a low, stable plasma plateau by ~2 weeks with no further accumulation [1] [2]. Age, immunocompromise and impaired hepatic function can change need for repeat dosing clinically, but pharmacokinetic details across age groups and in liver impairment are incompletely described in the available reporting (p1_s6; [7]; available sources do not mention detailed PK changes in elderly or liver failure beyond these clinical recommendations).
1. Oral vs topical: systemic exposure and accumulation
Clinical PK comparisons show oral ivermectin gives far higher systemic exposure than topical 1% cream; topical applications produce low plasma levels that "reached a plateau after 2 wk of repeated topical application" with no further accumulation during up to 1 year of treatment, while oral studies document measurable plasma concentrations and some accumulation depending on dose and dosing interval [2] [3]. High‑dose or more frequent oral regimens can raise AUC and Cmax, but even regimens giving repeated doses every fourth day showed only minimal accumulation (geometric mean AUC ratios day7/day1 ≈1.24 and 1.40 for 30 and 60 mg) indicating limited build‑up when dosing is spaced [1].
2. Repeated dosing: what accumulates and what isn’t clear
Multiple clinical and field studies document that repeated oral dosing can increase ivermectin exposure and pharmacodynamic effects; subcutaneous or serial dosing raised concentrations in some protocols (e.g., three subcutaneous doses produced serum levels up to 7.9 ng·ml−1 after the last dose) and mass drug administration trials use repeated high‑dose regimens for programmatic effect [3] [4]. However, controlled human escalation trials show that accumulation is generally modest when dosing intervals allow elimination, and topical regimens show early steady state with negligible further accumulation [1] [2]. Available sources do not provide a unified model of accumulation across all oral repeat schedules (daily, every‑other‑day, weekly) for standard human tablet dosing.
3. Formulation matters for safety signals and toxicity timing
Case series linked large or repeated oral (and veterinary) ivermectin exposures to toxicity, with some patients developing symptoms within hours after a single very large dose and others developing symptoms gradually after days to weeks of repeated dosing every other day or twice weekly — indicating both single massive doses and repeated supratherapeutic exposures can produce clinical toxicity [5]. Topical products have low systemic exposure in trials and long‑term dermatologic studies reported stable low plasma levels without accumulation over months [2].
4. Age and immune status: clinical dosing adjustments, limited PK data
Guidance documents and dosing guides note children above certain weight thresholds receive weight‑based oral doses and that people with weakened immune systems (including HIV) may require repeated therapy for parasitic clearance, but these sources focus on therapeutic strategy rather than detailed drug accumulation by age or frailty [6] [7] [8]. The onchocerciasis trial populations were adult males 18–60, so longitudinal PK/accumulation data in elderly, very young children, or pregnant women are not well characterized in the cited reports (p1_s3; available sources do not mention PK in elderly or severe pediatric/neonatal groups).
5. Liver function and metabolism: guidance vs evidence gap
Clinical summaries and dosing guides emphasize standard precautions and dose selection by body weight, but the provided sources do not supply quantitative data showing how hepatic impairment alters ivermectin clearance or accumulation in humans; therefore detailed claims about altered half‑life or fold‑increase in exposure with liver disease are not supported in the current reporting (p1_s5; available sources do not mention PK changes in hepatic impairment). Ivermectin undergoes hepatic metabolism (noted in broader PK reviews), but explicit human liver‑impairment accumulation data are absent from these search results (p1_s7; available sources do not mention measured PK in liver failure).
6. Practical takeaways and research gaps
Practically, expect negligible systemic accumulation with approved topical ivermectin and modest accumulation with oral regimens when dosing intervals exceed the elimination window; repeated dosing can increase systemic levels if dosing is frequent or high‑dose, and clinical toxicity has occurred with repeated supratherapeutic oral use [2] [1] [5]. Major gaps remain: the sources here do not quantify accumulation in elderly patients, in documented hepatic impairment, or across all repeat‑dosing schedules used in off‑label high‑dose regimens — those are areas where clinicians must rely on careful monitoring and limited trial data rather than definitive PK models (available sources do not mention detailed elderly or liver‑failure PK studies).
If you want, I can extract numeric PK parameters (half‑life, typical Cmax/AUC ranges) from the specific oral dosing studies cited here and map estimated accumulation for a few repeat schedules, noting uncertainty where primary data are missing.