Population pharmacokinetic modeling of plasma Δ9‐tetrahydrocannabinol and an active and inactive metabolite following controlled smoked cannabis administration

Abstract

Aims Population pharmacokinetic models of Δ9‐tetrahydrocannabinol (THC) have been developed for THC plasma and blood concentration data. Often, only the metabolites of THC are measurable when blood samples are obtained. Therefore, we performed a population pharmacokinetic analysis of THC, 11‐OH‐THC and THCCOOH plasma concentration data from a Phase I clinical trial of THC smoking. Methods Frequently obtained plasma THC, 11‐OH‐THC and THCCOOH concentration data were obtained over 168 h from 6 subjects who smoked low (15.8 mg) and high dose (33.8 mg) THC cigarettes on 2 occasions. Bayesian estimates of the THC pharmacokinetic model from each individual for each dose were fixed prior to the sequential pharmacokinetic analysis of the metabolites. Results A 3‐compartment model of THC was developed that has a steady‐state volume of distribution (VdSS) of 3401 ± 788 L and a clearance of 0.72 ± 0.10 L/min. 11‐OH‐THC was characterized by 50 ± 6% of the THC being directly cleared to a 3‐compartment model with a VdSS of 415.2 ± 4.3 L and clearance of 0.78 ± 0.05 L/min. The THCCOOH model shared the central compartment of the 11‐OH‐THC model with a VdSS of 29.1 ± 0.05 L and a clearance of 0.12 ± 0.02 L/min. First order kinetics were observed for THC and THCCOOH between the low and high doses, but a nonlinear pattern was observed for 11‐OH‐THC. Conclusion We describe the pharmacokinetics of THC, 11‐OH‐THC and THCCOOH including inter‐ and intraindividual variability of the parameter estimates of the model.

Population pharmacokinetic model of blood THC and its metabolites in chronic and occasional cannabis users and relationship with on‐site oral fluid testing

“…The volumes of distribution of THC at steady state and the elimination clearances were 2529 L and 1.06 L/min, 3719 L and 1.56 L/min with a dose of 10 and 30 mg, respectively. These results agree with Sempio et al's estimate of 3401 L and 0.72 L/min for doses of 15.8 and 33.8 mg 39 . Sempio et al identified an effect of dose on relative bioavailability, with a decrease in bioavailability of 0.89, 39 which we confirmed, as we found that that smoking 30 mg of THC led to a decrease in the relative bioavailability (F1) of 0.68 compared to a 10 mg dose.…”

“…These results agree with Sempio et al's estimate of 3401 L and 0.72 L/min for doses of 15.8 and 33.8 mg 39 . Sempio et al identified an effect of dose on relative bioavailability, with a decrease in bioavailability of 0.89, 39 which we confirmed, as we found that that smoking 30 mg of THC led to a decrease in the relative bioavailability (F1) of 0.68 compared to a 10 mg dose. This result is not fully explained by smoking behaviour (i.e., duration and depth of inhalation and exhalation, hold time in the lungs and time between puffs) because the smoking was standardized for all users.…”

“…Parameters derived from our model give an AUC, computed as dose/CL with CL = k10*V1, of 1600 μg*min/L for a dose of 10 mg which is within the 1420 and 2160 μg*min/L described in the Grotenhermen review 41 . Our three‐compartment model is also in agreement with another recently described in six subjects 39 . To compare with their results, we assumed a similar fraction absorbed of 0.25 and re‐parameterized our pharmacokinetic parameters (Table 2) in terms of a volume of distribution (sum of V1, V2 and V3) and an elimination clearance.…”

“…We found that the pharmacokinetic profile of THC after smoking 10 or 30 mg of THC presents a three‐phase decrease described by a three‐compartment model (Figure 1). This profile has already been described by studies using analytical techniques able to measure THC concentrations below 1 ng/mL 38,39 . Our study adds the link with two metabolites—11‐OH‐THC and THC‐COOH—allowing estimation of the constant rate transfer and the metabolite ratio.…”

The Impact of Marijuana on Antidepressant Treatment in Adolescents: Clinical and Pharmacologic Considerations

“…By contrast, the pharmacokinetics of inhaled THC are more variable, with up to 50% of inhaled smoke exhaled and some localized pulmonary metabolism. This results in a bioavailability of 10–25%, faster absorption (generally within minutes) [ 42 ], and inhaled THC exhibits first-order kinetics [ 43 ].…”