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

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 Cmax (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.

Pharmacokinetics in Animals and Humans of a First-in-Class Peptide Deformylase Inhibitor

ABSTRACT BB-83698, a potent and selective inhibitor of peptide deformylase, was the first compound of this novel antibacterial class to progress to clinical trials. Single- and/or multiple-dose studies with doses ranging from 10 to 50 mg of BB-83698/kg of body weight were done with mice, rats, and dogs. Intravenous pharmacokinetics were characterized by low to moderate clearances and moderate volumes of distribution for all species. In dogs, but not in rodents, central nervous system (CNS) effects were dose limiting for intravenously administered BB-83698 and were suspected to be related to a high maximum concentration of the agent in plasma (C max) rather than to total systemic exposure. Controlled infusion studies with dogs demonstrated that CNS effects could be avoided without compromising systemic exposure by reducing the C max. A randomized, double-blind, placebo-controlled, five-way-crossover, single-dose-escalation, phase I study to explore the safety, tolerability, and pharmacokinetics of intravenous BB-83698 at doses ranging from 10 to 475 mg was performed with healthy male volunteers. Systemic exposures were generally in linear relationships with administered doses in animals and humans. Pharmacokinetics were consistent, predictable, and exhibited good allometric scaling among all species (r 2 >0.98). Moreover, BB-83698 dosing in humans proceeded to a predicted efficacious exposure (the area under the concentration-time curve/MIC ratio, up to 184) without any clinically significant adverse effects.