How much does bioavailability of ivermectin increase when taken with fatty foods?
Executive summary
Clinical pharmacology studies disagree on the size of the food effect for oral ivermectin but converge on the direction: fatty (high‑fat) meals increase systemic exposure. Depending on the study population, dose and design, reported increases range from modest (≈18–37%) to large (≈2.5–2.6‑fold), with the official product label and several regulatory/clinical summaries citing roughly a 2.5‑fold increase after a standardized high‑fat meal [1] [2] [3] [4].
1. What the trials actually measured — and why results differ
Clinical pharmacokinetic (PK) analyses pooled small trials and report different magnitudes of food effect: a population PK model pooling two 12 mg single‑dose trials estimated a relative bioavailability of 1.18 (i.e., an ≈18% increase; 95% CI 1.10–1.67) when ivermectin was given after a high‑fat breakfast compared with fasting [1], while an earlier healthy‑volunteer study cited by multiple summaries (Guzzo et al.) found a ≈2.6‑fold increase in AUC with a high‑fat meal for fixed 30 mg doses [2]. Regulatory labelling and guidance (FDA/Merck/Stromectol® and WHO documents) adopt the larger effect for a 30 mg dose after a standardized 48.6 g‑fat meal, reporting an approximate 2.5‑fold increase in bioavailability [3] [5] [4].
2. Key drivers of the divergent estimates: dose, design and sample size
Differences in reported increases stem from dose and study design: the larger ≈2.5–2.6× increases were observed with 30 mg dosing in healthy volunteers and a defined high‑fat meal, whereas pooled analyses of mostly 12 mg dosing in patients with scabies found a far smaller mean effect (≈1.18) and even model‑identified subpopulations where no change was noted versus one group with a 37% increase [2] [1] [6]. Small sample sizes (some arms n≈3–12) and between‑study heterogeneity—health status, ethnicity, formulation and meal composition—drive variability and widen confidence intervals [1] [2].
3. Mechanistic plausibility: why fat matters for ivermectin
Ivermectin is highly lipophilic and relatively large, so ingestion with fats plausibly improves dissolution, micellar solubilization and uptake into chylomicrons and lymphatic transport—mechanisms that can materially boost oral absorption for hydrophobic drugs [2]. Animal and volunteer studies report higher AUC after fatty meals and note potential enterohepatic recycling and distribution into fatty tissues as complicating factors [7] [2].
4. Clinical and regulatory implications — consistency versus peak exposure
Regulatory labels and WHO guidance caution that a standardized high‑fat meal can raise exposure roughly 2.5‑fold for certain dosing conditions and therefore recommend consistent administration relative to meals to avoid unpredictable drug levels; however, some patient‑level PK models suggest the average food effect may be smaller, highlighting population heterogeneity [3] [5] [1]. The practical takeaway adopted by manufacturers and regulators errs on the side of caution because a 2.5× increase could change safety margins seen at higher doses [3] [4].
5. Limits of the evidence and unanswered questions
Available evidence is limited by small, heterogeneous trials, differing dose levels and meal definitions, and incomplete characterization of between‑subject variability; while labels rely on robust single studies for the 30 mg/high‑fat result, pooled patient data for lower doses show smaller average effects and subgroups with no change, so definitive quantification for all real‑world scenarios is lacking [1] [2] [6]. The literature documents the direction and plausible mechanisms; the exact magnitude depends on dose, meal composition and patient factors, and cannot be pinned to a single universally applicable number from the supplied sources [1] [2] [3].