In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models

Abstract

Gastrointestinal (GI) drug absorption is a complex process determined by formulation, physicochemical and biopharmaceutical factors, and GI physiology. Physiologically based in silico absorption models have emerged as a widely used and promising supplement to traditional in vitro assays and preclinical in vivo studies. However, there remains a lack of comparative studies between different models. The aim of this study was to explore the strengths and limitations of the in silico absorption models Simcyp 13.1, GastroPlus 8.0, and GI-Sim 4.1, with respect to their performance in predicting human intestinal drug absorption. This was achieved by adopting an a priori modeling approach and using well-defined input data for 12 drugs associated with incomplete GI absorption and related challenges in predicting the extent of absorption. This approach better mimics the real situation during formulation development where predictive in silico models would be beneficial. Plasma concentration-time profiles for 44 oral drug administrations were calculated by convolution of model-predicted absorption-time profiles and reported pharmacokinetic parameters. Model performance was evaluated by comparing the predicted plasma concentration-time profiles, Cmax, tmax, and exposure (AUC) with observations from clinical studies. The overall prediction accuracies for AUC, given as the absolute average fold error (AAFE) values, were 2.2, 1.6, and 1.3 for Simcyp, GastroPlus, and GI-Sim, respectively. The corresponding AAFE values for Cmax were 2.2, 1.6, and 1.3, respectively, and those for tmax were 1.7, 1.5, and 1.4, respectively. Simcyp was associated with underprediction of AUC and Cmax; the accuracy decreased with decreasing predicted fabs. A tendency for underprediction was also observed for GastroPlus, but there was no correlation with predicted fabs. There were no obvious trends for over- or underprediction for GI-Sim. The models performed similarly in capturing dependencies on dose and particle size. In conclusion, it was shown that all three software packages are useful to guide formulation development. However, as a consequence of the high fraction of inaccurate predictions (prediction error >2-fold) and the clear trend toward decreased accuracy with decreased predicted fabs observed with Simcyp, the results indicate that GI-Sim and GastroPlus perform better than Simcyp in predicting the intestinal absorption of the incompletely absorbed drugs when a higher degree of accuracy is needed. In addition, this study suggests that modeling and simulation research groups should perform systematic model evaluations using their own input data to maximize confidence in model performance and output.

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

“…After confirming that mixing of the organic layer with Level II FaSSIF components has minimal effect, if any, this study showed that biphasic experiments are useful for estimating PRC values of dipyridamole and ketoconazole. Based on the comparison of the resulted simulated plasma profiles with the actual plasma profiles in adults, estimations were better than those from the D-P data or the default values of the Simcyp software, which have previously been employed to model drug precipitation [47]. Biphasic experiments were also useful for estimating PRC values of itraconazole; for Sporanox ® OS, subsequent plasma simulations were better than using default PRC values in the Simcyp software.…”

Application of in Silico Tools in Clinical Practice using Ketoconazole as a Model Drug

“…Besides that, the pharmacokinetic parameters AUC, Tmax and Cmax were assessed in terms of the fold error between the observed and the predicted values, according to equation (1). As it is widely applied within pharmaceutical industries, a two-fold error was considered to be an acceptable prediction [46][47][48][49][50][51][52]…”

Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods

“…3), traditionally used in clinical trial design, are now being developed and used in earlier stages of discovery and development across industries. PBPK models require in vitro ADME data in addition to information about the physical and chemical properties of a compound reconstructed in vitro models (Muoth et al, 2016) to chip-based technologies (Picollet-D'hahan et al, 2016), new generation of parallel artificial membrane permeability assays (PAMPA) (Chen et al, 2008) and in silico modeling of gastrointestinal absorption approaches with validated commercial models (Gozalbes et al, 2011;Sjögren et al, 2016). An international group of experts in the field of epithelial barriers was convened from academia, industry, and regulatory bodies to present both the state-of-the-art of non-animal models of the skin, intestinal, and pulmonary barriers and to discuss research-based, industry-driven, and regulatory-relevant directions for both the development of new models and the refinement of existing test methods.…”