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By: Bart Hens, Shriram Pathak, Amitava Mitra

hens_photopathak-shriram_headshotOne of the promitro-amitava_headshotblems nowadays is the issue of low aqueous solubility for many drug candidates, synthesized in the earliest stage of oral drug development. Their poorly soluble characteristics will limit their oral absorption, resulting in a non-therapeutic outcome of the drug. To conquer this issue, formulation scientists rely on the concept of supersaturation in order to increase the drug’s systemic outcome.

Supersaturation refers to creation of supersaturated concentrations (i.e., concentrations higher than a drug’s solubility) at the level of the small intestine
, where intestinal absorption takes place. Creation of supersaturation can occur by two interesting approaches: by making use of supersaturating drug delivery systems or by transfer from stomach to small intestine. This second approach is only applicable for weakly basic compounds, which, due to their basic properties, may generate high concentrations in the acidic environment (pH 1-2) of the stomach. After transfer to the small intestine, which is in favor of a more neutral pH (6-7), these high concentrations of the drug that were generated in the process will start to precipitate until their level of solubility. The rate and extent of precipitation is dependent on the physicochemical identity of the compound itself as well as crucial physiological parameters, such as gastric emptying.

Within the framework of OrBiTo, a European project designed to develop a framework for optimal use of tools for better prediction of oral drug absorption, the physiologically based pharmacokinetics (PBPK) model Simcyp® Simulator has been explored to study intestinal supersaturation/precipitation, and the simulated data has been compared with intraluminal in vivo data in the Journal of Pharmaceutical Sciences article Supersaturation and Precipitation of Posaconazole Upon Entry in the Upper Small Intestine in Humans, with the aim to further optimize and validate this model and to enforce its predictive power.

In that report, the Simcyp® Simulator was applied to predict in vivo supersaturation and precipitation of a weak base, posaconazole, and compare against available clinical data after intragastric administration of two different suspensions of posaconazole. Gastric and duodenal concentrations were profiled as a function of time in parallel with systemic exposure. Based on this data, we were able to explore gastrointestinal dissolution, supersaturation, and precipitation of posaconazole in humans and its impact on systemic exposure.

In conclusion, the purpose of this study was to investigate the predictive power of the PBPK model Simcyp® Simulator to explore gastrointestinal luminal dissolution, supersaturation, precipitation, and systemic behavior of posaconazole after administration of two different suspensions in humans and to compare the predicted profiles with the observed profiles, derived from the clinical study. Predicted data by Simcyp® Simulator were compared with previously described clinical data. It was clearly demonstrated that predicted data were in line with the observed clinical data in terms of gastric dissolution, intestinal supersaturation, and the solid amount of posaconazole present in the upper small intestine. Supersaturated concentrations of posaconazole led to a higher systemic exposure for the acidified suspension compared to the neutral suspension.

This research should provide the basis for evaluation of supersaturation, precipitation, and systemic uptake for other basic drug compounds and/or supersaturating drug delivery systems.

Bart Hens, Ph.D., Shriram Pathak, Ph.D., and Amitava Mitra, Ph.D., all contributed to the European IMI project OrBiTo. Their focus was on intraluminal drug profiling of poorly soluble compounds after oral administration to humans. Based on these data, they evaluate in vitro and in silico models for their predictive power towards the in vivo outcome of the drug. Shriram Pathak works for Simcyp (a Certara company). Amitava Mitra works for Sandoz in clinical drug development. Bart Hens is a postdoctoral fellow at the University of Michigan and works with Gordon L. Amidon, Ph.D