Purpose: Regulatory agencies have encouraged the use of mechanistic absorption (MAM) and physiologically-based pharmacokinetic (PBPK) modeling to reduce both costs and time to market for new and generic drug products. The models require parameterization, and as such, many physicochemical parameters must be determined as a part of the development process. For low solubility weak bases with high solubility in gastric and low solubility in intestinal fluids, precipitation is an important aspect that requires evaluation. The simple in vitro transfer experiments have been shown to overestimate precipitation in vivo. The biphasic test incorporates an absorptive phase that is expected to lower supersaturation in a manner similar to in vivo and to provide more accurate precipitation estimates. In this work, we present an in silico model that is used to extract precipitation parameters from a biphasic in vitro dissolution test coupled with a MAM/PBPK model to predict precipitation in vivo. The goal was to test whether the biphasic in vitro assay provides more relevant parameters for in vivo extrapolation.
Methods: A mathematical model that accounts for simultaneous drug absorption into the organic phase and precipitation of the supersaturated drug solution in the aqueous phase was built in DDDPlus v6.0. The model was used to determine the precipitation parameters for itraconazole from the biphasic in vitro dissolution experiment. The physicochemical parameters for itraconazole used for the in vitro simulation are shown in Figure 1. The in vitro test was performed in a commercially available apparatus (InForm™) containing an aqueous phase of 40 mL phosphate buffer at pH 6.5 and 30 mL decanol organic receiver. The stirring rate was 100 rpm. The model calculates the mass transfer coefficient based on the rpm of the vessel. A 5 mg dose of Itraconazole was introduced to the aqueous phase as an acidified solution. Parameter optimization was utilized to determine the precipitation parameters (exponential correction and surface integration factor in the mechanistic nucleation model). The precipitation parameters were then utilized to predict Itraconazole precipitation in vivo using a previously developed Itraconazole MAM/PBPK model built in GastroPlus 1.
Results: The mechanistic precipitation parameters were fitted to the Itraconazole % dissolved vs. time profile in the in vitro biphasic dissolution experiment with R2 of 0.84 as shown in Figure 2. Values of 0.152 and 0.330 were obtained for the exponential correction and surface integration factor, respectively. The parameters were directly used in the previously built MAM/PBPK model in GastroPlus™ to predict behavior of two different formulations in human in fasted and fed conditions. The predicted and observed concentration-time profiles for a 200 mg solution and capsule administrations are shown in Figure 3. Three out of four scenarios were predicted accurately from in vitro data. The precipitation of itraconazole after administration of solution in fasted state is still overpredicted. However, the more advanced dissolution test with an absorptive phase seems to improve the overall in vitro to in vivo extrapolation of precipitation for the other 3 scenarios.
The advanced in vitro tests incorporating absorptive phase are a step forward in predicting in vivo precipitation from in vitro experiments when compared to simple transfer experiments and mechanistic in vitro and in vivo models are useful tools in the translation of in vitro measurements into in vivo predictions.
Viera Lukacova– Director– Simulation Sciences, Simulations Plus, Inc., Lancaster, California
Ke Szeto– Senior Scientist, Simulations Plus, Inc.
Micheal Bolger– Chief Scientist, Simulations Plus, Inc., Lancaster, California