Dose Estimation Utility in a Population Pharmacokinetic Analysis of Inhaled Δ9-Tetrahydrocannabinol Cannabis Market Products in Occasional and Daily Users

Abstract

Background: Unusually high variability in blood Δ9-tetrahydrocannabinol (THC) concentrations have been observed in subjects inhaling similar cannabis products over similar time periods when consumption is ad libitum. This makes simple gravimetric dose estimation a poor predictor of THC exposure. Population pharmacokinetic analyses of blood THC concentration versus time data are routinely used to estimate pharmacokinetic parameters. The aim of this study was to estimate the inhaled dose of THC in occasional and daily users of high potency market cannabis.

Methods: Blood THC concentrations were measured for 135 minutes from 29 participants who either smoked high concentration flower or inhaled concentrates ad libitum during a 15-minute session. Frequent blood samples were obtained over the following 135 minutes.

Results: The estimated central and rapidly equilibrating volumes of distribution of a 3-compartment model were 19.9 ± 1.2 and 51.6 ± 4.7 L whereas the intercompartmental clearances were 1.65 ± 0.14 and 1.75 ± 0.10 L/min, respectively. Covariate-adjusted analysis revealed that the estimated inhaled THC dose was considerably less among occasional users compared with daily users.

Conclusions: Three-compartment pharmacokinetics of THC did not differ among the 3 user groups, and the early phase (first 135 minutes postinception of inhalation) kinetics were similar to those previously described after smoking low potency cannabis products. Therefore, inhaled THC dose can be estimated from pharmacokinetic data and covariate-driven adjustments can be used to estimate THC doses, based on the participant cannabis usage pattern (occasional versus daily), improving the accuracy of THC exposure estimates compared with those derived from weighed THC content alone.

FIGURE 1.

Observed blood THC concentration versus time, beginning with the first postinhalation blood sample, for all 29 subjects (each line connects the measured concentrations from one subject) after subtraction of the baseline (before inhalation) blood THC concentration. Blue lines are occasional flower users, brown lines are daily concentrate users, and green lines are daily flower users.

FIGURE 2.

Final compartmental model used to fit plasma THC concentrations versus time. Drug is inhaled into VC of a 3-compartment THC model with rapidly and slowly equilibrating peripheral compartments V2 and V3, intercompartmental clearances Q2 and Q3, and elimination clearance CLe. Fi is the inhaled dose estimated as the fraction of a “standard” 15 mg absolute bioavailable THC dose. The *s signify model parameters which were fixed to the typical value estimates of those parameters from a previous study.

FIGURE 3.

A, Box plots of weighed THC doses with colors coded to match Figure 1. The dashed lines are the median values; the solid lines are the mean values. The ends of the “box” are the 25th and 75th percentiles. The whiskers show the lowest data value still within 1.5 IQR of the lower quartile and the highest value within 1.5 IQR of the upper quartile, whereas IQR is the interquartile range. B, Box plots of model-estimated inhaled THC doses with colors coded to match Figure 1. The dashed lines are median values; the solid lines are mean values. The ends of the “box” are the 25th and 75th percentiles. The whiskers show the lowest data value still within 1.5 IQR of the lower quartile and the highest value within 1.5 IQR of the upper quartile, whereas IQR is the interquartile range.

FIGURE 4.

Plot of weighed THC doses and model-estimated inhaled THC doses for all subjects. Circles represent the values for each individual and the black line is the linear regression through the origin.