What are the human pharmacokinetic thresholds for ivermectin associated with renal adverse events in case reports or pharmacovigilance databases?
Executive summary
There are no published human pharmacokinetic (plasma concentration or exposure) thresholds that reliably predict renal adverse events (AEs) after ivermectin; population pharmacovigilance and clinical studies report renal events as rare and without a clear dose–exposure relationship, while case reports describe isolated renal syndromes temporally linked to ivermectin but without measured drug concentrations to define thresholds [1] [2] [3] [4].
1. Pharmacokinetic baseline: how ivermectin is handled by the body
Ivermectin is highly lipophilic, extensively protein-bound and largely metabolized hepatically with biliary/fecal elimination; less than 1% of an administered dose is excreted unchanged in urine, and published clinical guidance generally states that renal impairment does not substantially change ivermectin clearance—supporting why routine dose adjustment for kidney disease is not typically required [5] [6].
2. Pharmacovigilance signal: what global safety databases show about renal events
A systematic case–non‑case pharmacovigilance analysis of WHO VigiBase reports from 2003–2020 found no detectable increase in reporting for renal disorders after ivermectin compared with other antinematodal drugs; sensitivity analyses likewise did not identify a robust association for renal AEs at the population level, meaning there is no pharmacovigilance-derived exposure threshold linking ivermectin to kidney injury [2] [1].
3. Clinical reports: isolated renal findings without PK measurements
Clinical literature and drug monographs note rare transient proteinuria and minor glomerular/tubular disturbances after ivermectin in onchocerciasis treatment, but these were described as minor and generally not clinically significant; importantly, these human reports do not provide plasma ivermectin concentration data or dose–exposure correlations that would establish a pharmacokinetic threshold for renal harm [7] [3].
4. Serious case reports: temporality, plausibility, and missing exposure data
There are case-level accounts suggesting more dramatic renal pathology temporally associated with ivermectin use—one report described a patient developing pauci‑immune necrotizing crescentic glomerulonephritis with features consistent with ANCA-associated vasculitis after prolonged ivermectin use—but these single cases lack measured ivermectin plasma levels, rechallenge data, or mechanistic biomarkers that would permit establishing a PK cut‑off linked to renal injury; causality remains possible but unproven [4].
5. Animal and experimental context: dose-dependent kidney changes seen in models, but human relevance is uncertain
Preclinical studies in rodents report histopathologic renal changes and oxidative/stress markers at exposures and dosing regimens that do not map simply onto standard human dosing, and while these raise biological plausibility for nephrotoxicity at high exposures, they do not provide human pharmacokinetic thresholds because interspecies scaling, route and dose differences, and absence of human concentration–effect data prevent direct translation [8] [9].
6. Practical interpretation: what clinicians and regulators can conclude now
Because ivermectin is minimally renally excreted and large pharmacovigilance datasets show no signal for renal disorders, there is currently no evidence-based plasma‑concentration or dose threshold in humans that predicts renal AEs; clinicians should therefore continue to follow standard dosing guidance (commonly ~200 µg/kg for approved indications), monitor clinically when prescribing to patients with multiple comorbidities or off‑label high‑dose use, and treat isolated case reports as signals warranting vigilance and further study rather than definitive proof of a PK threshold [5] [6] [1] [3] [4].
7. Limits of the record and next steps for research
The conclusion that no human PK threshold exists rests on the absence of measured ivermectin concentrations in reported renal cases and on pharmacovigilance analyses that rely on spontaneous reporting; targeted prospective pharmacokinetic–pharmacodynamic studies, measurement of plasma levels in serious renal cases, and systematic post‑marketing surveillance focused on high‑dose and off‑label use would be required to identify any exposure threshold—current sources do not provide those data, and some online summaries (e.g., AI‑generated overviews) reflect synthesis rather than primary measured PK results, a limitation noted in the literature available for this review [5] [6] [2].