Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling.

While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as 'not plausible'. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract.

Characterization of various deformable liposomes with metronidazole.

OBJECTIVE: The aim of this study was to investigate various deformable liposomes for their potential application for the vaginal administration of metronidazole. MATERIALS AND METHODS: Deformable liposomes composed of egg phosphatidylcholine (EPC) and various surfactants [sodium deoxycholate (SDCh), Tween 80 or Span 80] and conventional liposomes consisting of EPC and egg phosphatidylglycerol-sodium (EPG-Na) were prepared with and without metronidazole. Additionally, a freeze-thaw method was applied to both classes of vesicles (liposomes) containing the drug to improve its trapping capacity. All of the liposomes prepared were characterized and compared in terms of size, polydispersity, zeta potential, entrapment efficiency and their permeability on a Caco-2 cell monolayer. RESULTS AND DISCUSSION: Conventional liposomes, both with and without metronidazole, were larger than the deformable vesicles. The presence of ethanol in the preparations of the elastic EPC/SDCh and EPC/Tween 80 liposomes was found to affect the particle size in terms of reducing this parameter. Different types of vesicles were compared for their trapping efficiency of metronidazole and the highest entrapment was observed with conventional liposomes. However, deformable EPC/SDCh liposomes were found to enhance the permeability of metronidazole more effectively than the conventional liposomes based on the in vitro model of the epithelial barrier. CONCLUSION: These preliminary data indicate that EPC/SDCh liposomes may have a promising future in vaginal delivery of metronidazole. Therefore, additional investigations on elastic vesicles and their incorporation in a suitable vehicle should be considered to further evaluate their applicability in vaginal drug delivery.