Use of Artificial Stomach−Duodenum Model for Investigation of Dosing Fluid Effect on Clinical Trial Variability

Abstract

Lilly Compound X (LCX) is an oncology drug that was tested in a phase I clinical study using starch blend capsules. The drug was given to a small patient population (4 patients) and showed large inter- and intra-patient variability. In order to evaluate the possible effect of stomach pH on exposure and ways to mitigate the variability issue, artificial stomach-duodenum (ASD) experiments were conducted to investigate the hypothesis that carefully selected dosing fluids would have an impact in minimizing exposure variability caused by the formulation, which could lead to more consistent evaluation of drug absorption in patients. The ASD data corroborates the observed variability, and was a good tool to investigate the effect of stomach pH and potential dosing solutions on duodenal concentrations. Administering capsules co-formulated with Captisol (10% drug load) along with Sprite was shown by the ASD to be an effective way to increase duodenal concentrations as well as to reduce the difference between duodenal concentrations for different gastric pH. The reduction in variability of duodenum AUC (in ASD) is expected to correlate well with a reduction of variability in patient exposure. The dosing regimen of Sprite/Captisol is therefore suggested for future clinical trials involving LCX. Furthermore, for design of early phase clinical trials, ASD technology can be used to assist in choosing the proper dosing solution to mitigate absorption and exposure variability issues.

Assessing the performance of amorphous solid dispersions

“…80 Other two phase dissolution systems have been reported that attempt to mimic the GI tract (stomach and duodenum) to give a better correlation with bioavailability studies. [81][82][83] In one of these systems, 81 the crystallization of an amorphous form during dissolution was observed and the dissolution results still compared favorably with dog bioavailability studies. In our survey, the majority of studies used Apparatus 2 (71%) as shown in Figure 1a.…”

“…A number of studies show that the two-phase dissolution method employing both gastric and intestinal fluids can successfully predict the performance for oral solid forms. [81][82][83] It is also important to match the media with the proposed delivery route. In one study using suppositories, it is postulated that the lack of IVIVR was due to the smaller amount of in vivo fluid available in the animal model (rabbit) compared with that used in the dissolution test.…”

Influence of Particle Size on the Ultraviolet Spectrum of Particulate-Containing Solutions: Implications for In-Situ Concentration Monitoring Using UV/Vis Fiber-Optic Probes

“…An increasingly important alternative to these traditional techniques is the in situ measurement of dissolution profiles using fiber-optic UV/ Vis probes. These probes are also finding widespread use for concentration determination in applications such as the miniaturized analysis of (intrinsic) dissolution rates using a rotating disk (1,2) or powder (3), estimations of particle sizes based on dissolution rate data (4), and determination of precipitation behavior in artificial stomach-duodenum models (5).…”

Regulatory Considerations in Development of Amorphous Solid Dispersions

“…The most commonly used dissolution media are 0.1 N HCl, water, simulated gastric fluid without enzyme, simulated intestinal fluid without enzyme, and pH 6.8 buffer (Jantratid et al 2009;Newman et al 2012). It is also recommended to run the dissolution in two media that can predict in vivo performance of ASD, most preferably in simulated gastric and simulated intestinal fluid Polster et al 2010). However, when possible, surfactants and organic solvents-based dissolution media should be avoided as they would diminish the discriminating ability of the dissolution method.…”