Abstract
The pig has been increasingly used as a reliable preclinical model for assessing and predicting the in vivo bioavailability of different formulation strategies. Nevertheless, differences in the composition between porcine and human intestinal fluids, may impact on the solubility and dissolution behaviour of drugs, in particular BCS II/IV drugs. Recently, a porcine fasted simulated intestinal fluid (FaSSIFp) was developed to mimic the composition in the lumen of landrace pigs under fasted state conditions. In this work, we present the utilization of FaSSIFp to compare solubility against human FaSSIF & FeSSIF and further combine species specific in vitro testing with in silico predictive modelling. Venetoclax was chosen as a model drug, representing a BCS class IV drug, with a reported clinically significant positive food effect, where bioavailability is increased up to approximately five-fold when administered with a high-fat meal. Biorelevant species specific in vitro testing was a promising tool for integrating in vitro data into in silico models, using FaSSIFp resulted in reliable predictions of the plasma concentration profile in fasted pigs, based on a porcine physiologically based absorption model. The porcine physiologically based absorption model was used to prospectively simulate the impact of food on the bioavailability of venetoclax. The use of luminal solubility estimates in combination with dissolution data for venetoclax, measured in species specific simulated fluids, correctly predict the observed pig plasma concentration profile and food effect. Overall, integrating species specific in vitro – in silico models led to accurate prediction of in vivo absorption of venetoclax in a preclinical stage, which can support guidance in early decisions of drug product development. In addition, the study further demonstrated the utility of the pig model to predict the food effects of venetoclax in humans.
Highlights
Preclinical bioavailability predictions of new drug candidates require a thorough understanding of factors influencing drug absorp tion
We present the utilization of FaSSIFp to compare solubility against human Fasted state simulating intestinal fluid (FaSSIF) & fed state simulating intestinal fluid (FeSSIF) and further combine species specific in vitro testing with in silico predictive modelling
The solubility of venetoclax measured in FaSSIFp was 154 ± 15 μg/ mL, which is higher compared to human FaSSIF (5.2 ± 0.3 μg/mL) and can be attributed to the the higher bile salt concentrations in FaSSIFp, which is designed to mimic pig intestinal conditions in the fasted state (Henze et al, 2020)
Summary
Preclinical bioavailability predictions of new drug candidates require a thorough understanding of factors influencing drug absorp tion. Physiochemical characterisation of human intestinal fluids is well described (Augustijns et al, 2014) and the development of fluids to simulate either gastric (fasted state simulated gastric fluid, FaSSGF) or intestinal (fasted state simulated intestinal fluid, FaSSIF) contents is well documented (Jantratid et al, 2008; Vertzoni et al, 2005) These established biorelevant media, are routinely used for dissolution and solubility studies during drug development (Bergstrom et al, 2014; Klein, 2010). More recently a porcine biorelevant medium was established, based on fasted intestinal content characteristics of pigs (Henze et al, 2020) Both media are specially adapted to reflect species specific properties in the gastrointestinal tract, such as pH, buffer capacity, osmolality, surface tension and bile and phospholipid concentrations. The simulations showed that using human FaSSIF the observed drug plasma concentrations were under predicted for both formulations, while the canine biorelevant media clearly improved the predictions
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