Virtual Bioequivalence Assessment of Ritlecitinib Capsules with Incorporation of Observed Clinical Variability Using a Physiologically Based Pharmacokinetic Model.

Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.

DSC study of sucrose melting.

An early endothermic peak at approximately 150 degrees C was observed for crystalline sucrose by differential scanning calorimetry. The enthalpy at this temperature was found to vary with recrystallised sucrose from different sources. The addition of mineral salts to recrystallisation solutions decreased the enthalpy of the peak at around 150 degrees C, whereas the absence of salts increased it. The presence of organic solvents and polysaccharides in solution had a minor effect compared to the inorganic impurities. The peak was also depleted by increasing the amount of stirring and temperature at which recrystallisation was performed.