What are ivermectin’s pharmacokinetics after single vs repeated dosing in humans?
Executive summary
Single-dose oral ivermectin at typical antiparasitic regimens (150–200 μg/kg) reaches peak plasma concentrations within hours and shows long terminal elimination with reported half-lives ranging from about 24 hours in older reviews to 81–91 hours in at least one fixed‑dose volunteer study; ivermectin is highly lipophilic, >90% protein‑bound, widely distributed (Vd ~3.1–3.5 L/kg) and is eliminated mainly in feces with <1% urinary excretion [1] [2] [3] [4]. Repeated topical or repeated oral dosing can produce stable systemic exposures or accumulation depending on formulation and schedule: topical 1% cream showed steady systemic AUC by two weeks with similar exposure at day 14 and 28, whereas lipophilicity and adipose partitioning predict accumulation and prolonged redistribution after multiple or high doses [5] [2] [6].
1. What happens after a single oral dose — absorption, peak and redistribution
Human PK studies show rapid absorption with a biphasic plasma profile and a secondary rise 6–12 hours after a 150 μg/kg dose consistent with enterohepatic recycling; reported clinical single doses are 150 μg/kg (onchocerciasis) and 200 μg/kg (strongyloidiasis/scabies), and single‑dose PK has been used to judge safety and efficacy in mass‑drug campaigns [1] [7] [6]. The drug’s lipophilicity and protein binding (>90%) drive wide distribution into tissues, especially adipose, which creates a reservoir that can return drug to plasma as levels fall [2].
2. Half‑life and elimination — published ranges and their implications
Different studies report different terminal half‑lives: classic reviews and older data note an elimination half‑life “around a day” for many volunteers, while a clinical trial of fixed‑dose oral ivermectin reported half‑lives between 81 and 91 hours [1] [3]. Ivermectin metabolites and parent drug are largely excreted in feces over about 12 days with under 1% renal excretion; this fecal elimination aligns with hepatic metabolism via CYP3A and enterohepatic recycling seen in PK profiles [4] [8] [1].
3. Repeated dosing — steady state, accumulation and formulation matters
Topical repeated application (ivermectin 1% cream) produced stable systemic exposure by two weeks with AUC0–24h values essentially identical at day 14 and 28, indicating steady state for that route and regimen [5]. For oral repeated dosing, adipose partitioning and Vd (~3.1–3.5 L/kg) mean repeated or high oral dosing can lead to accumulation and prolonged apparent elimination; the literature documents efforts to design long‑acting formulations precisely because single doses can leave a long pharmacodynamic effect despite measurable plasma decline [2] [6].
4. Dose‑proportionality, high‑dose studies and safety signals
Controlled human escalation trials tested single oral doses up to 120 mg and repeat regimens (e.g., 30 or 60 mg three times weekly) and found dose‑related plasma AUCs and no clear CNS toxicity up to many times standard approved dosing, though PK metrics varied with fed versus fasted state and body composition [9] [10]. One trial with fixed 18 mg tablets reported half‑lives in the 81–91 h range and no serious adverse events across groups, underscoring that PK behavior at higher or repeated dosing has been directly studied [3].
5. PK vs PD — why measurable drug levels fall but effects persist
Clinical authors emphasize a disconnect: ivermectin’s plasma elimination may be relatively rapid compared with pharmacodynamic antiparasitic effects that can last months after a single dose; this is attributed to tissue retention, drug action at parasite sites and possibly active metabolites [1] [6]. Metabolite profiling after single oral 12 mg doses has been performed to assess activity against mosquitoes and to understand exposure beyond parent drug [8].
6. Limitations, disagreements and where reporting diverges
Reported half‑life estimates differ substantially across sources (≈24 h in earlier reviews versus ~81–91 h in some clinical PK studies), reflecting variation by assay, dose, population, fed state and analytic window [1] [3]. Available sources do not mention detailed comparative numeric Cmax/AUC values for every single vs repeated oral regimen across populations; they do document enterohepatic recycling, high protein binding and predominant fecal excretion [1] [4] [8]. Readers should note some sources are reviews synthesizing older primary studies while others are single clinical trials; each has implicit agendas—reviews summarize broad literature, clinical trials aim to support safety/labeling or new formulations [1] [3] [5].
7. Bottom line for clinicians and public health planners
Single oral doses (150–200 μg/kg) rapidly produce systemic exposure with biphasic profiles and potential enterohepatic re‑entry; lipophilicity and high Vd explain accumulation potential on repeated dosing and mismatches between plasma PK and long antiparasitic PD. Topical repeated dosing produces steady systemic exposure by two weeks for that formulation, and high‑dose escalation trials demonstrate tolerability but variable half‑life estimates that matter when designing repeat schedules or mass‑drug administration [1] [5] [3].
If you want, I can extract key numeric PK parameters (Cmax, Tmax, AUC, t1/2) from specific clinical trials cited here and present them side‑by‑side with dose and formulation.