Comprehensive Multi-Route, Multi-Formulation Population Pharmacokinetic Analysis of Δ9-THC and 11-OH-Δ9-THC

The pharmacokinetics of Δ9-tetrahydrocannabinol (THC) and its active metabolite 11-hydroxy-THC (11-OH-THC) vary substantially across routes of administration and formulations and are altered by cannabidiol (CBD) if co-administered. However, no population pharmacokinetic model has integrated and quantified these factors. We developed a simultaneous parent–metabolite nonlinear mixed-effects model using data from 369 participants consisting of 12,112 THC and 11-OH-THC observations across 17 clinical studies upon intravenous, smoked, vaporized, and oral (brownie, soft gel, tablet) administration. THC disposition was described by a three-compartment model (CL, 43.5 L/h; Vss, 268 L). Bioavailability was 2.4-fold higher for vaporized than for smoked THC (28.7% vs. 12.0%), and oral bioavailability was low (brownie, 6.6%; tablet, 4.8%). Approximately 12% of systemic THC clearance formed 11-OH-THC, whereas 42% of absorbed oral THC was converted to 11-OH-THC during first pass, making presystemic conversion the main source of 11-OH-THC after oral dosing. 11-OH-THC disposition was described by a three-compartment model (CL, 13.4 L/h; Vss, 431 L). High-dose CBD co-administration (CBD-to-THC ratios of 18:1 to 32:1) increased oral THC bioavailability approximately 2.5- to 3.5-fold and reduced 11-OH-THC clearance by approximately 76%, consistent with CBD inhibition of cannabinoid-metabolizing enzymes. This model provides a quantitative framework to support pharmacokinetic–pharmacodynamic modeling and to inform dose optimization, formulation development, and safety evaluation of cannabis-derived products.