How do pharmacokinetics of ivermectin differ between oral tablet, paste, topical and injectable formulations across species?
Executive summary
Ivermectin’s pharmacokinetics are dominated by slow absorption, wide tissue distribution, low metabolic clearance and slow excretion, but those broad traits are heavily modulated by route and formulation—oral tablets produce different peak concentrations and apparent half-lives than pour‑on (topical), injectable (aqueous or non‑aqueous), or paste preparations, and those differences vary by species [1] [2]. Vehicle composition, administration route and species physiology (fat content, rumen/skin differences) are the principal drivers of bioavailability, Cmax, AUC and t1/2, making simple cross‑species extrapolation unreliable [1] [3].
1. Absorption: oral tablets and pastes versus topical and injectable—who gets into the blood fastest?
Oral ivermectin (tablets or pastes) is absorbed relatively slowly but predictably in humans and many animals, with absorption profiles shaped by formulation and feeding status, while topical “pour‑on” products give highly variable and often lower systemic availability because cutaneous penetration and grooming cause unpredictable uptake and cross‑contamination; injectable products can be tuned by vehicle to give either rapid systemic input (aqueous) or prolonged, slow release (nonaqueous) [4] [5] [6].
2. Distribution and metabolism: lipophilicity and species differences control where the drug goes
Ivermectin’s high lipophilicity drives broad distribution and retention in fatty tissues, producing longer apparent volumes of distribution and longer t1/2 in species or individuals with higher adipose stores; species differences in metabolism and transporters (including ABC transporters) also alter systemic exposure and metabolite profiles, and human studies report enterohepatic recycling that can cause secondary rises in plasma levels after oral dosing [7] [8] [4].
3. Half‑life and clearance: the anatomy of persistence across species
Measured biological half‑lives vary markedly by species—classic reviews report t1/2 increasing roughly from swine (~0.5 day) to dogs (~1.8 day) to cattle and sheep (~2.8 day) under comparable conditions—while formulation can further extend apparent half‑life (for example, certain nonaqueous injectable vehicles produce much longer t1/2 due to prolonged absorption; one reported t1/2 of ~8.3 days for a slow‑release injectable vehicle) [9] [6] [10].
4. Formulation matters: vehicles, variability and controlled‑release strategies
Multiple sources emphasize that the vehicle used in injectables or topical gels drives bioavailability and duration—mixed aqueous–organic vehicles yield intermediate PK profiles, purely nonaqueous solvents produce controlled‑release kinetics, and pour‑on formulations show high interanimal variability and unpredictability, which has clinical implications for persistence of effect and selection pressure for resistance [6] [5] [11].
5. Species and context limit extrapolation: ruminants, monogastrics and humans are not interchangeable
Rumen physiology, skin thickness, grooming behavior and fat composition produce distinct PK outcomes: ruminants often show longer persistence and different Cmax/AUC patterns than monogastric species; human PK after oral tablets is relatively well characterised and more reproducible in trials, but animal data cannot be directly transposed to humans or across animal species without accounting for route and vehicle [3] [4] [1].
6. Practical implications: efficacy windows, dosing decisions and resistance risk
Because route and formulation determine systemic exposure and persistence, choosing an injectable nonaqueous product can lengthen the therapeutic window while pour‑on topical treatments may produce subtherapeutic systemic levels or variable protection—both clinical efficacy and the epidemiology of resistance will therefore depend on matching species, formulation and administration route rather than assuming a universal ivermectin PK profile [2] [5] [11].
7. Limits of available reporting and open questions
The reviewed literature consistently flags extensive interstudy and interproduct variability—vehicle composition, brand differences, feeding state and animal condition are repeatedly cited as confounders—meaning precise parameter values (Cmax, exact t1/2 for given formulation in a given species) require study‑level data rather than summary generalities, and the sources do not provide a single standardized cross‑species table that could be quoted without caveats [12] [1] [13].