Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging

Abstract

Basmisanil, is a lipophilic drug substance, exhibiting poor solubility and good permeability (BCS class 2). A validated physiologically based biopharmaceutics model (PBBM) has been previously described for tablets dosed in the fed state. The PBBM captured the less than proportional increases in exposure at higher doses well and indicated that absorption was dissolution rate-limited below 200 mg while solubility was limiting for higher doses. In this study, a model for dosing in the fasted state is described and is verified for simulation of the food effect where exposures were ~1.5 fold higher when a 660 mg tablet was given with food. The model is then applied to simulate the food effect for a granules formulation given at a lower dose (120 mg). The food effect at the lower dose was reasonably simulated with a ratio of simulated/observed food effect of 1.35 for Cmax and 0.83 for AUC. Sensitivity analysis was carried out for uncertain model parameters to confirm that the model could predict the magnitude of the positive food effect with moderate to high confidence. This study suggests that a verified PBBM can provide a useful alternative to a repeat food effect study when formulation changes are minor. However, there is need for further evaluation of the approach and a definition of what formulation changes are minor in this context. In addition, this work highlights some uncertainties in the handling of solubility in PBBM, in particular around temperature dependency of solubility and the parameterization of bile salt solubilization using measurements in biorelevant media.

Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants

“…The role of in silico tools has become evident not only in drug design, where their contribution is unquestionable, but also in supporting the selection of specific drugs and determining the appropriate timing for their administration [33,62]. These findings also open up the possibility of broadening the spectrum of B-RAF inhibitor-sensitive variants beyond mutations at codon V600.…”

“…Starting from the observation of a clinical response to targeted therapy in a patient with B-RAF T599dup mutant melanoma, we applied ligand-based homology modeling to both mutant proteins using a B-RAF-V600E X-ray structure as a template. Indeed, computerbased approaches have been widely used in drug discovery and development [33][34][35][36], both to speed up the identification of promising therapeutically relevant molecules [37][38][39] and to rationalize experimental outcomes [40][41][42]. This approach allowed for a threedimensional structure of both the rare B-RAF mutated proteins with a pocket accessible to Dabrafenib and V600E.…”