Aim: Cannabis-based medicines are gaining interest and being explored for new therapeutic indications, many of which commonly affect older medical patients. As most previous studies of the population pharmacokinetics of cannabinoids have been performed in healthy adults, this study aimed to investigate the population pharmacokinetics of THC and its active metabolite 11-hydroxy-Δ9-tetrahydrocannabinol (THC-OH) in older medical patients with poor appetite. Methods: We administered two fixed doses of Sativex® oromucosal spray to 20 patients, each dose consisting of 2 or 3 sprays (2.7 mg THC and 2.5 mg cannabidiol per spray), with a dosing interval of four hours. Blood samples were collected for up to eight hours to obtain plasma concentration-time data for non-linear mixed-effects modeling. Population pharmacokinetic models were developed for THC and THC-OH sequentially, resulting in a combined parent-metabolite model. Results: We found a one-compartment model and a two-compartment model to be the best fits for THC and THC-OH, respectively, with apparent clearance of THC through conversion to THC-OH (765 L/h) and other pathways (162 L/h). Absorption of THC was modeled with a delay through three transit compartments. The inter- and intra-individual variability on pharmacokinetic parameters was generally large (CV% = 40.2-152%). Using the parent-metabolite model, it was investigated whether physiological characteristics such as kidney function and body composition influence THC pharmacokinetics. Conclusion: the parent-metabolite model describes and quantifies the pharmacokinetics of oromucosally administered THC in older medical patients with poor appetite. The covariate analysis did not show any clinically significant effect on pharmacokinetic parameters of THC or THC-OH.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different compositions of microparticle formulations called LIQ865. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modeling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for bupivacaine clearance at higher doses. Bupivacaine clearance and the transit rate constant describing the slow absorption process both decreased with increasing doses following a power function with a shared covariate effect of dose on the two parameters. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine, and the biphasic absorption seen for several local anesthetics.