069: Population Pharmacokinetic Model of Delta-9-Tetrahydrocannabinol (THC) & Metabolites in Healthy Adults Following Single Oral Dose

Statement of Purpose: The use of recreational cannabis has been growing in recent years across the US after the expansion of marijuana legalization among multiple states. Of which, oral cannabis products, a relatively new delivery of recreational cannabis, gained particular popularity over smoking/vaping due to the more substantial drug effects and more discreet administration. The primary psychoactive compound of cannabis is delta-9-tetrahydrocannabinol (THC). Studies found that THC undergoes first-pass metabolism following oral consumption to 11-OH-Δ9-tetrahydrocannabinol (11-OH-THC), which is more psychoactive than THC. THC pharmacokinetics has been extensively studied in smoking/vaping products, while only a handful of oral THC PK was reported. Although several population PK models for THC and its metabolites have been reported, most of them focused on characterizing their disposition following i.v. or inhalation, which cannot be adapted directly for oral THC products due to the additional complexity introduced during absorption process (e.g., fist-pass metabolism to generate more active metabolite). To fill this literature gap, we aimed to develop a population pharmacokinetic model of THC and its metabolites to quantitatively characterize THC disposition in human following oral THC administration.

Description of Methods & Materials: The clinical plasma PK data for THC and its metabolites, 11-OH-THC and 11-Nor-9-carboxy-Δ9 -tetrahydrocannabinol (THC-COOH), were obtained from two published studies in 35 healthy subjects using cannabis brownies containing 10, 25 or 50 mg of THC. All the THC and its metabolites PK data were analyzed simultaneously using the non-linear mixed effect modeling with NONMEM (v7.4.1) interfaced with Pirana. The first-order conditional estimation method with interaction (FOCEI) and a user-defined subroutine (ADVAN13) were used. The interindividual variability and residual variability were evaluated using an exponential model and a combined additive and proportional error model, respectively. SigmaPlot (v14.0) was used for data visualization and analysis. The final model was selected based on the success of model convergence, the precision of parameter estimates and goodness-of-fit plots.

Data & Results: Among all the models tested, the final model for THC and its metabolites consisted of one depot compartment, one compartment for THC, and one compartment each for 11-OH-THC and THC-COOH, with first-order elimination for all three compounds. A first-order metabolic rate constant (Kgut) was added from the depot compartment to the 11-OH-THC compartment to address the first-pass metabolism. The apparent volume of distribution (Vd/F) for THC, 11-OH-THC, and THC-COOH were estimated to be 533 L, 101 L, and 2.12 L, respectively. The apparent clearance (CL/F) for THC, 11-OH-THC, and THC-COOH were estimated to be 1160 L/hr, 265 L/hr, and 4.15 L/hr, respectively. The fraction of THC converted to 11-OH-THC (Fm1) was reported as 0.24, the fraction of 11-OH-THC converted to THC-COOH (Fm2) was 0.151, and Kgut was reported to be 0.00024 hr-1.

Interpretation, Conclusion or Significance: Our model successfully captured the THC, 11-OH-THC, and THC-COOH pharmacokinetics following oral THC. This model provided valuable quantitative insight into oral THC disposition. With this model set as a starting point, our next step is to build a comprehensive model using data from all different routes of administration as well as from various biomatrix such as urine, oral fluid and human tissue.

Disclosures: The authors have no conflict of interests to disclose.