Pharmacokinetics and Tolerability of Δ9-THC-Hemisuccinate in a Suppository Formulation as an Alternative to Capsules for the Systemic Delivery of Δ9-THC

Abstract

The objectives of this study were: (1) to assess the safety, tolerability, and pharmacokinetics of ascending doses of Δ⁹-tetrahydrocannabinol-hemisuccinate (THC-HS) after rectal administration as suppositories in male volunteers; and (2) to compare the pharmacokinetics of oral administration of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) with an equivalent amount of Δ⁹-THC delivered as THC-HS via the suppository formulation. In support of the pharmacokinetic evaluations, an analytical method was developed and validated for the determination of Δ⁹-THC and for its major circulating metabolites 11-hydroxy-Δ⁹-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ⁹-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in human plasma. Δ⁹-THC, 11-OH-THC, and THC-COOH were extracted from plasma using solid phase extraction and analyzed by liquid chromatography-tandem mass spectrometry. The limits of detection and quantitation for all 3 analytes were 0.25 and 0.5 ng/mL, respectively. The method was validated over the range of 0.5–25 ng/mL. This method was used to quantify Δ⁹-THC and any THC-HS as Δ⁹-THC due to the inclusion of a hydrolysis step as part of the extraction procedure. Therefore, Δ⁹-THC measured was the total THC (free Δ⁹-THC plus Δ⁹-THC derived from THC-HS). The assay was reproducible for the measurement of all 3 analytes, with a variability of 7.2, 13.7, and 8.3%, respectively, at the 1 ng/mL level. The method was then used to assess the pharmacokinetics of Δ⁹-THC and metabolites from the suppository dosage form in doses equivalent to 1.25, 2.5, 5, 10, and 20 mg Δ⁹-THC per suppository as THC-HS. Systemic exposure to Δ⁹-THC, administered as THC-HS suppository, increased broadly dose proportionally. Systemic exposure and C_{max (obs)} estimates for 11-OH-THC and THC-COOH generally increased subproportionally. The pharmacokinetic profiles of Δ⁹-THC and metabolites were also compared after oral administration of 10 mg Δ⁹-THC (as dronabinol capsules) and after administration of 10 mg equivalents of Δ⁹-THC as THC-HS in suppository form. Total systemic exposure to Δ⁹-THC was considerably higher following rectal administration of THC-HS than after oral administration. The Δ⁹-THC area under the plasma concentration versus time curve (AUC_(0–_∞₎) for THC-HS was 2.44-fold higher (90% confidence interval: 1.78, 3.35) than for the capsule administration.