Kuentz, Martin

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Kuentz
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Martin
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Kuentz, Martin

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2018 - 20192
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Autor:in: Litou, Chara ×

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    Publikation
    Combining biorelevant in vitro and in silico tools to simulate and better understand the in vivo performance of a nano-sized formulation of aprepitant in the fasted and fed states
    (Elsevier, 01.10.2019) Litou, Chara; Kuentz, Martin [in: European Journal of Pharmaceutical Sciences]
    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.
    01A - Beitrag in wissenschaftlicher Zeitschrift
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    Publikation
    In vitro methods to assess drug precipitation in the fasted small intestine – a PEARRL review
    (Wiley, 06/2018) O'Dwyer, Patrick J.; Litou, Chara; Box, Karl, J.; Dressman, Jennifer; Kostewicz, Edmund, S.; Kuentz, Martin; Reppas, Christos [in: Journal of Pharmacy and Pharmacology]
    Objectives Drug precipitation in vivo poses a significant challenge for the pharmaceutical industry. During the drug development process, the impact of drug supersaturation or precipitation on the in vivo behaviour of drug products is evaluated with in vitro techniques. This review focuses on the small and full scale in vitro methods to assess drug precipitation in the fasted small intestine. Key findings Many methods have been developed in an attempt to evaluate drug precipitation in the fasted state, with varying degrees of complexity and scale. In early stages of drug development, when drug quantities are typically limited, small‐scale tests facilitate an early evaluation of the potential precipitation risk in vivo and allow rapid screening of prototype formulations. At later stages of formulation development, full‐scale methods are necessary to predict the behaviour of formulations at clinically relevant doses. Multicompartment models allow the evaluation of drug precipitation after transfer from stomach to the upper small intestine. Optimisation of available biopharmaceutics tools for evaluating precipitation in the fasted small intestine is crucial for accelerating the development of novel breakthrough medicines and reducing the development costs. Summary Despite the progress from compendial quality control dissolution methods, further work is required to validate the usefulness of proposed setups and to increase their biorelevance, particularly in simulating the absorption of drug along the intestinal lumen. Coupling results from in vitro testing with physiologically based pharmacokinetic modelling holds significant promise and requires further evaluation.
    01A - Beitrag in wissenschaftlicher Zeitschrift