Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling

Abstract

Abstract. Effective integration of in vitro tests and absorption modeling can greatly improve our capability in understanding, comparing, and predicting in vivo performances of clinical drug products. In this case, we used a proprietary drug candidate galunisertib to describe the procedures of designing key in vitro tests, analyzing relevant experimental and trial data, and integrating them into physiologically based absorption models to evaluate the performances of its clinical products. By simulating the preclinical study result, we estimated high in vivo permeability for the drug. Given the high sensitivity of its solubility to pH, supersaturation may play an important role in the absorption of galunisertib. Using the dynamic dissolution test, i.e., artificial stomach-duodenum (ASD) model and simulation, we concluded galunisertib in solution or tablet products could maintain supersaturation during the transit in the gastrointestinal tract (GIT). A physiologically based absorption model was established by incorporating these key inputs in the simulation of Trial 1 results of galunisertib solution. To predict the performance of three tablet products, we developed z-factor dissolution models from the multi-pH USP dissolution results and integrate them into the absorption model. The resultant biopharmaceutical models provided good prediction of the extent of absorption of all three products, but underestimated the rate of absorption of one tablet product. Leveraging the ASD result and optimization with the dissolution model, we identified the limitation of the model due to complexity of estimating the dissolution parameter z and its in vitro-in vivo correlation.

Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

“…The compound demonstrated the highest solubility near pH 2, which corresponds to the fasted stomach pH, and maintained favorable solubility and dissolution properties for absorption at pH 4.5 and pH 7.5, as observed in duodenal and intestinal fluids. When these solubility data were applied to a gastroduodenal passage model (39), the simulation predicted that LY3023414 would closely approach the theoretical maximum absorption in contrast to other PI3K/mTOR dual inhibitors (i.e., NVP-BEZ-235 and PF04691502; see Supplementary Fig. S1), whereas absorption would be only slightly reduced by coadministration of gastric pH-altering proton-pump inhibitors.…”

Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer

“…In these in vitro experiments, the PK profiles of the RC formulations were similar to that of the HSWG formulation [9]. …”

“…Galunisertib is well absorbed with peak plasma concentrations attaining around 0.5–2 hours following administration and with mean terminal half-life of 8 hours [8]. The effect of gut pH on galunisertib absorption has been studied previously, where we reported that galunisertib in solution or tablet products maintained supersaturation during transit in the gastrointestinal tract [9]. To reduce the impact of change in pH after a meal, galunisertib has thus far been administered to patients only in fasted state.…”

“…Therefore, the RBA study compared API of two different particles sizes (x90 of 50 μm and x90 of 80 μm) and two different oral solid manufacturing platforms (HSWG and RC). It was expected that the in vivo PK profile of the 3 tablet presentations would be similar based on in vitro experiments [9]. However, a clinical evaluation was necessary for further clinical development of these galunisertib formulations.…”

In vitro methods to assess drug precipitation in the fasted small intestine – a PEARRL review

“…The initial starting volumes in the chambers, the flow rate of fresh media into the chambers and the emptying rate from the chambers can all be adjusted to fit the experimental requirements (e.g. in vitro modelling of fasted/fed state, human or dog model) . Dilute HCl and Level II FaSSIF are typically used as gastric and duodenal fluid, respectively.…”