Predicting oral bioavailability (F oral The OrBiTo database was found to be largely representative of previously published datasets.)43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.
Keywords:Physiologically-based pharmacokinetics (PBPK); modelling and simulation (M&S); absorption; oral bioavailability (F oral ); biopharmaceutics; drug database
The target of this article is to summarize the chemical and pharmaceutical (formulation) approaches that were found to be suitable for increasing the bioavailability of a model weak base (SAR1) with a very narrow good solubility range at physiologically relevant pH. 1 As part of the preformulation and formulation development to support toxicological and first in man studies of a free base (SAR1), several formulation approaches, including particle size reduction, emulsions, permeability enhancers, amorphous dispersions, salt formation, and co-crystal formation, were screened by in vitro dissolution methods and in vivo pharmacokinetic (PK) studies to evaluate and rank formulation performance. From the PK studies, it was observed that a suspension formulation containing a SAR1 fumaric acid (1:1) co-crystal provided the best oral exposure. Sensitivity of the co-crystal to physical disintegration into base and fumaric acid was solved by including Cremophor ELP as a solubility enhancer, surfactant, and co-crystal protector. This formulation was well-tolerated in rat. A flow-through dissolution method was more discriminating than the paddle type dissolution equipment for evaluation of co-crystal containing solid formulations.
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