Artemisinin Cocrystals for Bioavailability Enhancement: Part 2. In-vivo Bioavailability and PBPK Modelling

We report the evaluation and prediction of the pharmacokinetic (PK) performance of artemisinin (ART) cocrystal formulations, i.e., 1:1 Artemisinin-Orcinol (ART-ORC) and 2:1 Artemisinin-Resorcinol (ART2-RES), using in vivo murine animal and PBPK (physiological based pharmacokinetic) models. The efficacy of the ART cocrystal formulations along with the parent drug ART were tested in mice infected with Plasmodium berghei. When given at the same dose, the ART-cocrystal formulation showed a significant reduction in parasitaemia at day 4 post infection compared to ART alone. The PK parameters including Cmax (maximum plasma concentration), Tmax (time to Cmax), AUC (area under the curve) were obtained by determining drug concentrations in the plasma using LC-HRMS (Liquid Chromatography-High Resolution Mass Spectrometry), showing enhanced ART levels after dosage with the cocrystal formulations. The dose-response tests revealed that a significantly lower dose of the ART cocrystals in the formulation was required to achieve a similar therapeutic effect as ART alone. A PBPK model was developed using a PBPK mouse simulator to accurately predict the in vivo behaviour of the cocrystal formulations by combining in vitro dissolution profiles with the properties of the parent drug ART. The study illustrated that information from classical in vitro and in vivo experimental investigations of the parent drug of ART formulation can be coupled with PBPK modelling to predict the PK parameters of an ART cocrystal formulation in an efficient manner. Therefore, the proposed modelling strategy could be used to establish in vitro and in vivo correlations for different cocrystals intended to improve dissolution properties and to support clinical candidate selection, contributing to assessment of cocrystal developability and formulation development.