Fed-state simulating intestinal fluid FeSSIF

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

The study was performed with a Class 1 member in the form of tablets. Changes in pH have no effects while changes in agitation intensity for USP apparatus II and IV have shown clear influences on the tablet erosion and subsequently on its release. Finally to simulate the fasted and fed state in vivo, fasted state stimulated intestinal fluid(Fassif) and fed state simulated intestinal fluid(Fessif) media were used. None of the USP traditional apparatus show a clear relationship with the in vivo results, especially in the fed conditions. In vitro data obtained by the ADS in the fasted state were consistent with those in vivo, as well as in the fed state after a slight time adjustment allowed in the FDA notes of guidance. A Level A of IVIVC was easily established with a good correlation coefficient in the fasted and fed states, respectively. The main results are presented in Fig. 13. 

Table 2. Composition of fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) (Galia et al., 1998, Vertzoni et al., 2004).

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