3.2 | Pharmacokinetic Parameters
The PK assessment of a single dose of 2.5 mg each of Δ9-THC and CBD (2 sprays on Day 1) versus a single dose of 7.5 mg each of Δ9-THC and CBD (six sprays on Day 2) was investigated for all participants in Stage I. The PK parameters calculated for Δ9THC, CBD and Δ9-THC metabolites, 11-OH-THC and COOH-THC, are presented in Table 2. There was a rapid uptake of Δ9-THC and CBD, as indicated by detectable plasma levels at the first 30 minute time point following oro-mucosal administration (Figure 2) and cannabinoids having a mean tmax of 0.88 hours (Table 2). Single doses of Δ9-THC and CBD were rapidly eliminated, with 2.5 mg of Δ9-THC and CBD eliminated in just under 1 hour and 45 minute, respectively, and approximately twice that duration for the higher 7.5 mg dose (Table 2). The plasma concentration of the main active metabolite of Δ9-THC, OH-THC, peaked soon after Δ9-THC (0.12 and 0.4 hours after Δ9-THCfor the low and high dose, respectively) and persisted for approximately three-fold longer (OH-THC t1/2 was 3.4 and 5 hours for the low and high dose, respectively). Mean plasma concentrations of Δ9-THC, CBD, OH-THC and COOH-THC were approximately proportional to dose, with a six-fold high dose providing a 2.8-, 3.2- 3.0- and 3.6-fold higher area under the curve (AUC) and a 1.4-, 1.5-, 1.8- and 2.6-fold high Cmax, respectively (Table 2). The single ascending dose PK analysis of this study showed that Cmax and bioavailability was always higher for Δ9-THC than for CBD. For the 2.5 mg Δ9-THC/2.5 mg CBD dose, the Cmax of Δ9-THC was 1.58 ng mL−1 1.5-fold higher than the 1.02 ng mL−1 for CBD; and the AUC(0-t) of
Δ9-THC was 2.79 ng mL.hr−1, 1.9-fold higher than the 1.46 ng mL.h−1 for CBD (Table 2). Furthermore, as the concentration of the drug was increased from 2 sprays on day 1 to 6 sprays on day 2, there was an increased change in the plasma con cen trations of Δ9-THC and CBD that demonstrated a n.on-linear PK behaviour.