What are the pharmacokinetics of ivermectin in humans, including absorption, distribution, metabolism, and excretion?
Executive summary
Ivermectin is administered orally in humans and shows variable absorption influenced by formulation and food; typical plasma Cmax occurs several hours after dosing and elimination half-life is long (reported as roughly 12–36 hours in human studies) [1] [2] [3]. Ivermectin is highly lipophilic, distributes widely into tissues, is metabolized primarily by hepatic CYP enzymes (notably CYP3A isoforms) and is excreted mainly in feces with minimal unchanged urinary elimination; formulation, dose and host genetics affect exposure [1] [2] [4] [5].
1. How people take it — route, absorption and formulation effects
Humans receive ivermectin almost exclusively by mouth; the literature and reviews state the oral route is the only approved human administration route in clinical practice [1] [2]. Absorption is influenced by formulation and by whether the drug is taken with food: studies comparing tablets, capsules and oral solution report similar Cmax and AUC for solid forms but higher systemic availability with an oral solution, implying formulation can change bioavailability [6]. Dose-escalation and population PK studies describe first-order or mixed absorption models, with Tmax (time to peak concentration) occurring a few hours after dosing in typical single-dose studies [1] [5] [3].
2. Tissue life — distribution and lipophilicity
Ivermectin is highly lipophilic and distributes beyond plasma into tissues; both one- and two-compartment PK models have been used to describe its disposition in humans, reflecting an initial distribution phase followed by a slower elimination phase [1]. Animal work and human PK reviews note substantial tissue binding and preferential distribution to fat, consistent with long apparent volumes of distribution reported in PK summaries [1] [7]. Distribution also depends on transport proteins: research and database summaries note ivermectin interacts with human ABC transporters such as ABCG2 and is a substrate affected by P‑glycoprotein systems in preclinical models, which can alter tissue penetration and safety [4].
3. The body’s processing plant — metabolism
Human-focused reviews and PK analyses identify hepatic metabolism as the primary clearance pathway. CYP3A enzymes are implicated in ivermectin biotransformation; variability in CYP and transporter genotypes (e.g., MDR1/ABCB1, CYP3A4/5) is discussed as a plausible reason for interindividual differences in exposure [2] [8] [4]. Metabolites have been studied in the context of vector control: human trial samples were analyzed to characterize metabolites and their possible biological activity, which bears on both efficacy against parasites and effects on feeding mosquitoes [9].
4. How it leaves — excretion and half-life
Clinical PK reports indicate elimination is relatively slow. Human studies including dose-escalation trials report prolonged terminal phases, with half-life estimates in the literature spanning approximately a day or more (sources summarize long elimination phases; see human PK reviews and clinical studies) [1] [3]. The dominant route of excretion is biliary/fecal; unchanged drug in urine is minimal, consistent with hepatic metabolism and fecal elimination described in reviews [1] [7]. Exact numeric ranges depend on dose, formulation and study population [3] [6].
5. Dose, special regimens and high‑dose data
Most licensed human uses employ single low doses (~0.15–0.2 mg/kg for many parasitic indications), but clinical trials have safely tested substantially higher or repeated doses (e.g., single doses up to 120 mg and repeated regimens in controlled studies) and reported tolerability with corresponding PK characterization [3] [10]. Population PK work on fixed-dose combinations (ivermectin + albendazole) used two-compartment models with more complex absorption descriptions and showed exposure scales with body weight [5].
6. Uncertainties, controversies and why context matters
Available reviews and trials document interstudy variability in PK parameters and note gaps: human PK data are sparser and less consistent than animal datasets, and genetics (MDR1, CYP3A variants) and formulation choices create meaningful exposure differences [1] [2] [8]. Some research explores metabolites’ biological roles (e.g., mosquito lethality), but whether metabolites fully explain post‑ivermectin effects is an active area of study [9]. Drug databases and reviews warn against extending PK findings to unsupported indications; for instance, DrugBank underscores that high‑quality clinical efficacy/safety data are required before repurposing beyond approved uses [4].
Limitations: available sources do not provide a single harmonized table of numeric PK parameters for every regimen; readers should consult the primary clinical PK studies cited here for exact Cmax, Tmax, t1/2 and AUC values for specific doses and formulations [1] [3] [6].