What are pharmacokinetic differences of ivermectin in low body weight versus obese patients?
Executive summary
Ivermectin’s pharmacokinetics are shaped by its high lipophilicity, producing clear differences between low‑body‑weight (including undernourished children) and obese subjects: obese individuals tend to have larger volumes of distribution and prolonged elimination, while low‑weight or malnourished patients can show higher systemic exposure per dose [1] [2]. Animal and modeling work imply that maintenance doses in obesity may be better scaled to lean body weight and loading doses to total body weight, but human clinical guidance is limited and conflicting evidence exists from fixed‑dose human trials [3] [4] [5].
1. Lipophilicity drives redistribution and increases volume of distribution in obesity
Ivermectin is highly lipophilic and therefore partitions into adipose tissue, which increases the apparent volume of distribution (Vd) and leads to accumulation with more prolonged elimination as drug redistributes from fat back to plasma; this mechanism is documented in reviews and pharmacology summaries and helps explain why volunteers with higher BMI display different PK patterns [1] [6].
2. Reduced clearance per kg and longer half‑life in obese models
When clearance is scaled to total body weight, obesity reduces apparent plasma clearance substantially in experimental models — the canine obesity model reported decreases of ~42–55% (and up to 63% for related compounds) when expressed per kg — and obesity produced increased absolute Vd, implying longer terminal half‑lives [4] [7] [8].
3. Implications for dosing: lean‑weight for maintenance, total weight for loading (animal evidence)
Investigators using an obese dog model concluded that maintenance dosing for ivermectin (and moxidectin) should be calculated on lean body weight, whereas loading doses, when required, should be based on total body weight; this recommendation stems from observed unchanged or reduced total clearance and markedly increased Vd in obesity [9] [3] [4].
4. Human trial data are mixed: fixed‑dose studies vs BMI associations
Human pharmacokinetic trials of fixed dosing (18 mg tablet studies) showed that systemic exposure metrics (AUC, Cmax) were not consistently associated with BMI or total weight, yet BMI and weight correlated with t1/2 and apparent V/F, suggesting retention in adipose tissue affects elimination even if peak exposure was similar across weight groups [5] [10] [6].
5. Low body weight and undernutrition can increase exposure in children
Pediatric PK studies found that undernourished preschool and school‑age children had higher AUCs at the same mg/kg dosing and that weight‑adjusted clearance was higher in children than adults, indicating that low body weight and nutritional status alter exposure—and that standard per‑kg dosing does not fully normalize systemic exposure across ages and nutritional states [2] [11].
6. Mechanistic modeling flags absorption variability and biliary dependence
Physiologically based PK (PBPK) models emphasize that ivermectin absorption is sensitive to bile‑micelle–mediated solubility and that BMI is associated with t1/2 and total apparent clearance; these mechanistic insights mean that both body composition and formulation/meal effects can modify exposure beyond simple weight scaling [6].
7. Clinical relevance, caveats and competing interpretations
While animal and PBPK work strongly suggest obese patients will have increased Vd and longer elimination and therefore might require dose adjustments (maintenance by lean body weight), human clinical data are limited and not unanimous: some human studies of fixed dosing find AUC and Cmax similar across BMI groups, and regulatory dosing for many indications still uses total body weight or fixed‑dose bands [5] [3] [12]. Existing canine data cannot be assumed fully translatable to humans without further clinical PK/PD studies [4].
8. Practical takeaways and unanswered questions
The weight of evidence supports expecting larger Vd and prolonged half‑life in obesity and potentially greater exposure in underweight/malnourished patients, meaning dose‑scaling solely by total body weight can misestimate exposure; however, formal human dosing recommendations for obese patients are not established and require targeted PK studies and safety assessments before changing practice [3] [5] [4].