Cannabidiol (CBD) has multiple therapeutic benefits that need to be maximized by optimizing its bioavailability. Numerous formulations are therefore being developed and their pharmacokinetics need to be studied, requiring analytical methods and data from intravenous administration. As CBD is susceptible to hepatic metabolism, the requirement of any method is to quantify metabolites such as 7-COOH-CBD. We demonstrated that CBD and 7-COOH-CBD could be simultaneously and correctly quantified in piglet plasma by using an UHPLC–MS/MS technique. The validated method allowed for an accurate bioanalysis of an intravenously injected solution consisting of CBD-HPβCD complexes. The experimental pharmacokinetic profile of CBD showed multi-exponential decay characterized by a fast apparent distribution half-life (0.25 h) and an elimination half-life of two hours. The profile of 7-COOH-CBD was not linked with the first-pass metabolism, since 80% of the maximum metabolite concentration was reached at the first sampling time point, without any decrease during the period of study. A two-compartment model was optimal to describe the experimental CBD profile. This model allowed us to calculate macro–micro constants and volumes of distribution (V_ss = 3260.35 ± 2286.66 mL) and clearance (1514.5 ± 261.16 mL·h⁻¹), showing that CBD is rapidly distributed to peripheral tissues once injected and slowly released into the bloodstream.

This study aimed to link pharmacokinetic (PK) data from different flurbiprofen preparations for the treatment of sore throat with published data to elucidate whether early efficacy is due to the local action of flurbiprofen or a systemic effect after absorption of the swallowed drug. Three comparative bioavailability studies conducted in healthy subjects provided data from flurbiprofen 8.75 mg formulations, including spray solution, spray gel, lozenges, and granules. A parallel interstudy comparison was made of PK parameters, including partial AUCs (pAUCs), using an ANOVA model with the calculation of 90% confidence intervals (CI) for the differences between least squares (LS) means for each of the test groups versus the respective reference groups. All three studies showed bioequivalence for the respective product comparisons. The interstudy comparison showed a slower rate of absorption for granules compared to spray solution (reference) based on T_max, C_max, and pAUCs for 1 h and 2 h. When AUC_0.25h and AUC_0.5h were considered, slower rates of absorption were also seen for lozenges and spray gel. The differences correlated with the reported time of onset of action, which is faster for the spray solution (20 min) compared to lozenges (26 min) and granules (30 min). These pAUCs provide useful data that allow for the discrimination between formulations. Moreover, the pAUC values represent <5% of the total AUC, suggesting that the early onset of pain relief is a response to immediate local absorption at the site of action rather than a systemic effect.

Background: Cannabidiol (CBD) shows interesting therapeutic properties but has yet to demonstrate its full potential in clinical trials partly due to its low solubility in physiologic media. Two different formulations of CBD (amorphous and lipid-based) have been optimized and enable an increase in bioavailability in piglets. In vivo studies are time-consuming, costly and life-threatening. Therefore, we need to develop in vitro tests that can predict what will happen in vivo. Methods: Comparisons in terms of dissolution were made especially by using different media (FaSSGF, FaSSIF, FeSSIF, HCl 0.1N with or without SLS, phosphate buffer pH 6.8 with or without SLS) and different conditions (sink or non-sink conditions). These in vitro results were confronted with in vivo results to select the most appropriate dissolution test conditions. Results: The importance of the presence of surfactants to enable solubilization of CBD was demonstrated. Neutral media enabled a relatively good prediction of the extent of absorption observed in vivo, whereas the rate of absorption was more complicated to predict. Conclusions: FeSSIF media, and FaSSIF sink media to a lesser extent, were the only compositions enabling predictions of both extent and rate, indicating that emulsification is possibly a major contributor to the in vivo availability of the drug.

Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model exists, a comparative clinical study can be performed in healthy subjects; where no surrogate endpoint is available, patients with the relevant indication need to be enrolled, with all the associated factors which could result in lack of sensitivity. Even though the need for alternative in vitro approaches has been acknowledged by both industry and regulatory bodies, the complexity of in vivo drug delivery processes makes the development of guidance documents particularly difficult. Our objective was to present in vitro approaches less classically used and to address in vivo relevance of the selected tests. Methods: This article analyses current regulatory approaches in Europe and the U.S., and highlights the key advantages of in vitro tests in terms of their sensitivity, reliability, reproducibility and in vivo relevance using locally applied flurbiprofen in various formulations. Results: The in vitro esophageal retention (IVOR) model demonstrates that the first 6–10 min after application of different flurbiprofen formulations is important for their comparison and also offers the best correlation with in vivo data using the partial area under the concentration-time curves (pAUCs). Rheological evaluations further demonstrated that the mucoadhesive properties of the gel spray formulation are based on interaction with mucin. Conclusions: Designing a relevant in vitro test requires adequate evaluation of the complexity of the drug substance, drug product, dosing conditions and delivery processes.