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Introduction: In the development of bio-enabling formulations, innovative in vivo predictive tools to understand and predict the in vivo performance of such formulations are needed. Etravirine, a non-nucleoside reverse transcriptase inhibitor, is currently marketed as an amorphous solid dispersion (Intelence® tablets). The aims of this study were 1) to investigate and discuss the advantages of using biorelevant in vitro setups in simulating the in vivo performance of Intelence® 100 mg and 200 mg tablets, in the fed state, 2) to build a Physiologically Based Pharmacokinetic (PBPK) model by combining experimental data and literature information with the commercially available in silico software Simcyp® Simulator V17.1 (Certara UK Ltd.), and 3) to discuss the challenges when predicting the in vivo performance of an amorphous solid dispersion and identify the parameters which influence the pharmacokinetics of etravirine most.
Methods: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp® Simulator, using in vitro results and data available from the literature as input. The impact of pre- and post-absorptive parameters on the pharmacokinetics of etravirine was investigated using simulations of various scenarios.
Results: In vitro experiments indicated a large effect of naturally occurring solubilizing agents on the solubility of etravirine. Interestingly, supersaturated concentrations of etravirine were observed over the entire duration of dissolution experiments on Intelence® tablets. Coupling the in vitro results with the PBPK model provided the opportunity to investigate two possible absorption scenarios, i.e. with or without implementation of precipitation. The results from the simulations suggested that a scenario in which etravirine does not precipitate is more representative of the in vivo data. On the post-absorptive side, it appears that the concentration dependency of the unbound fraction of etravirine in plasma has a significant effect on etravirine pharmacokinetics.
Conclusions: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to advance our knowledge in the field of bio-enabling formulations. Future studies on other bio-enabling formulations can be used to further explore this approach to support rational formulation design as well as robust prediction of clinical outcomes.
Introduction: When developing bio-enabling formulations, innovative tools are required to understand and predict in vivo performance and may facilitate approval by regulatory authorities. EMEND® is an example of such a formulation, in which the active pharmaceutical ingredient, aprepitant, is nano-sized. The aims of this study were 1) to characterize the 80 mg and 125 mg EMEND® capsules in vitro using biorelevant tools, 2) to develop and parameterize a physiologically based pharmacokinetic (PBPK) model to simulate and better understand the in vivo performance of EMEND® capsules and 3) to assess which parameters primarily influence the in vivo performance of this formulation across the therapeutic dose range.
Methods: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp Simulator, informed by the in vitro results and data available from the literature.
Results: In vitro experiments indicated a large effect of native surfactants on the solubility of aprepitant. Coupling the in vitro results with the PBPK model led to an appropriate simulation of aprepitant plasma concentrations after administration of 80 mg and 125 mg EMEND® capsules in both the fasted and fed states. Parameter Sensitivity Analysis (PSA) was conducted to investigate the effect of several parameters on the in vivo performance of EMEND®. While nano-sizing aprepitant improves its in vivo performance, intestinal solubility remains a barrier to its bioavailability and thus aprepitant should be classified as DCS IIb.
Conclusions: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to understand and predict the absorption of this poorly soluble compound from an enabling formulation. The approach can be applied to other poorly soluble compounds to support rational formulation design and to facilitate regulatory assessment of the bio-performance of enabling formulations.
Background: Drugs used to treat gastrointestinal diseases (GI drugs) are widely used either as prescription or over23 the-counter (OTC) medications and belong to both the ten most prescribed and ten most sold OTC medications worldwide. Current clinical practice shows that in many cases, these drugs are administered concomitantly with other drug products. Due to their metabolic properties and mechanisms of action, the drugs used to treat gastrointestinal diseases can change the pharmacokinetics of some co27 administered drugs. In certain cases, these interactions can lead to failure of treatment or to the occurrence of serious adverse events. The mechanism of interaction depends highly on drug properties and differs among therapeutic categories. Understanding these interactions is essential to providing recommendations for optimal drug therapy.
Objective: To discuss the most frequent interactions between GI and other drugs, including identification of the mechanisms behind these interactions, where possible.
Conclusion: Interactions with GI drugs are numerous and can be highly significant clinically. Whilst alterations in bioavailability due to changes in solubility, dissolution rate and metabolic interactions can be (for the most part) easily identified, interactions that are mediated through other mechanisms, such as permeability or microbiota, are less well understood. Future work should focus on characterizing these aspects.