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How does repeated dosing of ivermectin affect tissue accumulation and plasma levels?
Executive summary
Repeated dosing of ivermectin can modestly raise and sustain plasma concentrations and produces higher concentrations in some tissues (for example, lungs show ~3× plasma levels in animal studies), but human data show limited accumulation with standard antiparasitic regimens and a mean residence time of days rather than weeks [1] [2]. Pharmacokinetic reviews report volumes of distribution consistent with tissue partitioning and clinical reports of repeated dosing regimens (e.g., single doses repeated for scabies/oncocerciasis or short multi‑day courses) but note that optimal long‑term frequency and accumulation patterns remain unsettled [2] [3] [4].
1. How ivermectin distributes: central volume, tissue partitioning, and residence time
Ivermectin has a relatively large apparent volume of distribution and a mean residence time on the order of days, which indicates significant tissue uptake beyond plasma; in healthy men Vc was ~3.1–3.5 L·kg−1 and, in patients with onchocerciasis, a larger area volume (Vλ) of ~9.9 L·kg−1 with an MRT of about 3.7 days [2]. Review articles synthesize this pharmacokinetic pattern and conclude that tissue distribution is similar between healthy volunteers and infected patients, implying that tissue accumulation is a predictable feature of the drug at clinical doses [2].
2. Repeated dosing: what the human data show about plasma accumulation
Controlled human pharmacokinetic studies and reviews generally report only modest or no drastic accumulation in plasma with short repeated dosing schedules. For example, subcutaneous regimens in volunteer studies produced serum levels that rose during dosing but did not show “significant accumulation” over the subsequent days in the datasets cited by the mini‑review [2]. Clinical dosing guidance commonly treats ivermectin as a single‑dose therapy for many parasitic indications, with repeat doses used on an interval basis rather than continuous high‑frequency dosing [3] [4].
3. Tissue concentrations can exceed plasma—animal and model evidence
Animal and modelling studies cited in clinical trials suggest that some tissues (notably lung) can reach higher ivermectin levels than plasma—one animal synthesis cited three‑fold higher pulmonary tissue levels than plasma at one week after oral dosing [1]. Some pharmacokinetic models even predict up to tenfold accumulation in target tissues under certain assumptions, a point highlighted in the context of in vitro antiviral concentration debates [5]. These findings explain why investigators sometimes argue that tissue concentrations, not plasma levels alone, determine biologic activity.
4. Clinical dosing patterns and reasons for repeat dosing
Guidelines and drug compendia reflect that single doses are standard for many infections, but repeat dosing is recommended in particular clinical scenarios: scabies may be treated with repeat dosing after 1–2 weeks, onchocerciasis often requires repeated rounds of therapy over months or years because adult parasites aren’t killed, and immunocompromised patients with strongyloidiasis may need multiple courses [3] [4] [6]. These repeat schedules are based on parasitologic considerations and clinical response rather than an expectation of indefinite tissue accumulation to higher steady‑state plasma levels [4] [3].
5. Safety, high‑dose trials, and what accumulation implies for toxicity
High‑dose escalation studies have been performed to assess tolerability and pharmacokinetics in humans, and reviews note limited adverse effects at standard doses; nevertheless, toxicity (including neurologic events) is linked mechanistically to P‑glycoprotein interactions that normally limit CNS exposure, and animal models lacking that transporter show brain accumulation and toxicity—highlighting that tissue accumulation in privileged sites could drive risks under some conditions [7]. Clinical materials therefore advise adherence to recommended dosing intervals and monitoring, especially when retreatment is considered [7] [4].
6. Limits of the available reporting and competing interpretations
Available sources show consistency that ivermectin partitions into tissues and that repeated short courses can raise levels for days, but they disagree implicitly about how much tissue accumulation might be achieved relative to in vitro concentrations invoked in antiviral studies: some modelling papers predict up to 10× tissue accumulation [5] while pharmacokinetic reviews and human studies emphasize modest plasma accumulation and an MRT of days [2] [1]. Reported animal tissue:plasma ratios (e.g., ~3× for lung) provide context but do not automatically validate claims that standard oral dosing achieves the micromolar concentrations used in some cell‑culture antiviral experiments [1] [5].
7. Practical takeaways for clinicians and researchers
Clinically, repeated dosing is used when parasitologic biology requires retreatment (onchocerciasis, scabies, immunocompromised strongyloidiasis) rather than to drive indefinite plasma accumulation; pharmacokinetic studies show tissue partitioning and days‑long residence time but not unchecked plasma build‑up with typical regimens [4] [2] [3]. For translational or off‑label uses that hinge on tissue concentrations (for example, antiviral hypotheses), the literature recommends caution: animal tissue data and some models suggest higher tissue levels, but human pharmacokinetics and safety considerations currently limit how aggressively dosing can be escalated without targeted clinical trials [1] [5].
If you want, I can extract the specific plasma concentrations and time‑course numbers reported in the human pharmacokinetic studies cited (for example, mean ng·ml−1 values over time) and display them side‑by‑side with the animal tissue ratios.