posted on 2021-11-08, 22:04authored byManreet Kaur, Vanessa Yardley, Ke Wang, Jinit Masania, Randolph R. J. Arroo, David B. Turner, Mingzhong Li
We report the evaluation and prediction
of the pharmacokinetic
(PK) performance of artemisinin (ART) cocrystal formulations, that
is, 1:1 artemisinin/orcinol (ART-ORC) and 2:1 artemisinin/resorcinol
(ART2-RES), using in vivo murine animal
and physiologically based pharmacokinetic (PBPK) models. The efficacy
of the ART cocrystal formulations along with the parent drug ART was
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 after infection compared
to ART alone. PK parameters including Cmax (maximum plasma concentration), Tmax (time to Cmax), and AUC (area under
the curve) were obtained by determining drug concentrations in the
plasma using liquid chromatography–high-resolution mass spectrometry
(LC-HRMS), 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 behavior 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 formulations can be coupled with PBPK modeling
to predict the PK parameters of an ART cocrystal formulation in an
efficient manner. Therefore, the proposed modeling 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 the assessment of cocrystal developability and formulation development.