How do ivermectin pharmacokinetics vary with weight, age, and P‑glycoprotein inhibitors in humans?
Executive summary
Ivermectin’s pharmacokinetics are influenced by body composition and age in ways that often affect distribution and timing more than peak systemic exposure, while P‑glycoprotein (P‑gp) activity and CYP3A4-mediated metabolism can modulate tissue distribution and central nervous system penetration—especially when P‑gp is inhibited or genetically reduced [1] [2] [3] [4]. Human data are limited and sometimes contradictory: several clinical studies find no consistent effect of weight on AUC/Cmax but do show longer half‑life and larger apparent volume in heavier or higher‑BMI subjects, and pediatric populations show slower absorption and later Tmax [1] [5] [6].
1. Weight and body composition reshape distribution, not necessarily peak exposure
Clinical trials using fixed and weight‑based doses report that systemic exposure markers (AUC0‑t and Cmax) often do not correlate with body weight or BMI, meaning heavier individuals do not consistently have lower peak plasma levels after standard doses [1]. At the same time, ivermectin’s high lipophilicity produces greater retention in adipose tissue: BMI and weight have been associated with longer terminal half‑life (t1/2) and larger apparent volume of distribution (V/F), which implies longer tissue residency and a prolonged tail of plasma concentrations in people with more adipose tissue [1] [7]. Population PK analyses used for mass‑drug administration modeling therefore treat body composition as a driver of distribution kinetics rather than simple dose dilution [5] [7].
2. Age alters absorption timing and clearance patterns—children are not small adults
Pediatric PK work shows that children—particularly preschool and school‑aged groups—can exhibit delayed absorption and later Tmax than adults, probably due to differences in gastrointestinal motility and transit time, which are slower in younger children and can prolong uptake [2] [6]. Published pediatric studies of ascending ivermectin doses found distinct Tmax and sometimes different exposure profiles compared with adults, and PBPK models explicitly incorporate age‑dependent physiology to reproduce observed differences [6] [7]. Notably, some adult studies comparing healthy volunteers to onchocerciasis patients did not find major systemic PK differences at the same mg/kg dose, though enterohepatic recycling produced secondary plasma rises in both groups [8].
3. P‑glycoprotein controls intestinal and blood–brain handling; inhibitors matter
Ivermectin is a substrate of intestinal and blood–brain barrier efflux transporters, notably P‑gp (MDR1/ABCB1), which pumps absorbed drug back into the gut lumen and limits CNS accumulation; drugs or genetic variants that reduce P‑gp function can therefore increase tissue and brain exposure [3] [4]. Animal and in vitro studies demonstrate that absence or inhibition of P‑gp increases ivermectin accumulation in brain and other tissues, and co‑administration of P‑gp inhibitors (or drugs that inhibit both CYP3A4 and P‑gp) has been linked to higher systemic and CNS levels or altered tissue distribution in model systems [4] [9]. Human trials commonly exclude participants taking CYP3A4 or P‑gp interacting drugs because of this risk, and clinical PK research has genotyped MDR1 polymorphisms that correlate with altered bioavailability [5] [3].
4. CYP3A4 interactions are intertwined with P‑gp effects
Ivermectin is metabolized primarily by CYP3A4 (with contributions from CYP3A5 and CYP2C9), so inhibitors or inducers of these enzymes can change parent‑drug exposure and metabolite formation; because many CYP3A4 inhibitors also impair P‑gp, their combined effect may amplify systemic and brain exposure [10] [3]. Animal studies and mechanistic reviews suggest that some observed increases in ivermectin levels with co‑medications (e.g., ketoconazole in non‑humans) may be due more to P‑gp inhibition than to direct CYP blockade, but human clinical interaction data remain sparse [9] [10].
5. Limits, uncertainties, and competing agendas in the literature
The evidence base in humans is incomplete: many PK studies are small, exclude subjects on common interacting drugs, and rely on single‑dose data; PBPK modeling fills gaps but depends on assumptions about tissue binding, enterohepatic recycling and transporter kinetics [5] [7]. Public and policy interest in repurposing ivermectin (e.g., for malaria vector control) has driven higher‑dose and population‑scale modeling that raises interaction concerns and highlights where drug‑drug interactions or age/body‑composition effects could become clinically relevant—an implicit agenda that pushes for conservative exclusion of interacting medications in trials [3] [7]. Given these limits, definitive quantitative rules for dose adjustment by weight, age, or interacting drugs in all clinical contexts cannot be established from the cited human studies alone [1] [6] [4].