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Combining biorelevant in vitro and in silico tools to investigate the in vivo performance of the amorphous solid dispersion formulation of etravirine in the fed state.
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2020-03-07 , DOI: 10.1016/j.ejps.2020.105297 Chara Litou 1 , David B Turner 2 , Nico Holmstock 3 , Jens Ceulemans 3 , Karl J Box 4 , Edmund Kostewicz 1 , Martin Kuentz 5 , Rene Holm 3 , Jennifer Dressman 6
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2020-03-07 , DOI: 10.1016/j.ejps.2020.105297 Chara Litou 1 , David B Turner 2 , Nico Holmstock 3 , Jens Ceulemans 3 , Karl J Box 4 , Edmund Kostewicz 1 , Martin Kuentz 5 , Rene Holm 3 , Jennifer Dressman 6
Affiliation
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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 to simulate 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 of 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 etravirine in 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 by simulating 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.
中文翻译：
结合生物相关的体外和计算机工具来研究依曲韦林无定形固体分散体制剂在进食状态下的体内性能。
简介 在生物赋能制剂的开发中，需要创新的体内预测工具来理解和预测此类制剂的体内性能。依曲韦林是一种非核苷逆转录酶抑制剂，目前以无定形固体分散体（Intelence®片剂）的形式上市。本研究的目的是 1) 调查和讨论使用生物相关体外装置模拟 Intelence® 100 mg 和 200 mg 片剂在进食状态下的体内性能的优势，2) 建立基于生理学的药代动力学 (PBPK) ) 通过将实验数据和文献信息与市售计算机软件 Simcyp® Simulator V17.1 (Certara UK Ltd.) 相结合来建立模型，以及 3) 讨论预测无定形固体分散体体内性能的挑战并确定对依曲韦林药代动力学影响最大的参数。方法 在模拟胃肠道禁食和进食状态环境的各种生物相关介质中进行溶解度、溶出度和转移实验。使用体外结果和文献中的数据作为输入，在 Simcyp® 模拟器中开发了健康志愿者中依曲韦林的计算机 PBPK 模型。通过模拟各种情况，研究吸收前和吸收后参数对依曲韦林药代动力学的影响。结果 体外实验表明天然存在的增溶剂对依曲韦林的溶解度有很大影响。有趣的是，在 Intelence® 片剂溶出实验的整个过程中，观察到依曲韦林的过饱和浓度。 将体外结果与 PBPK 模型耦合提供了研究两种可能的吸收情况的机会，即有或没有实施沉淀。模拟结果表明，依曲韦林不沉淀的情况更能代表体内数据。在吸收后方面，血浆中依曲韦林未结合部分的浓度依赖性似乎对依曲韦林药代动力学具有显着影响。结论本研究强调了结合体外和计算机生物制药工具来提高我们在生物赋能制剂领域的知识的重要性。未来对其他生物赋能制剂的研究可用于进一步探索这种方法，以支持合理的制剂设计以及对临床结果的稳健预测。
更新日期：2020-04-21
中文翻译：
结合生物相关的体外和计算机工具来研究依曲韦林无定形固体分散体制剂在进食状态下的体内性能。
简介 在生物赋能制剂的开发中，需要创新的体内预测工具来理解和预测此类制剂的体内性能。依曲韦林是一种非核苷逆转录酶抑制剂，目前以无定形固体分散体（Intelence®片剂）的形式上市。本研究的目的是 1) 调查和讨论使用生物相关体外装置模拟 Intelence® 100 mg 和 200 mg 片剂在进食状态下的体内性能的优势，2) 建立基于生理学的药代动力学 (PBPK) ) 通过将实验数据和文献信息与市售计算机软件 Simcyp® Simulator V17.1 (Certara UK Ltd.) 相结合来建立模型，以及 3) 讨论预测无定形固体分散体体内性能的挑战并确定对依曲韦林药代动力学影响最大的参数。方法 在模拟胃肠道禁食和进食状态环境的各种生物相关介质中进行溶解度、溶出度和转移实验。使用体外结果和文献中的数据作为输入，在 Simcyp® 模拟器中开发了健康志愿者中依曲韦林的计算机 PBPK 模型。通过模拟各种情况，研究吸收前和吸收后参数对依曲韦林药代动力学的影响。结果 体外实验表明天然存在的增溶剂对依曲韦林的溶解度有很大影响。有趣的是，在 Intelence® 片剂溶出实验的整个过程中，观察到依曲韦林的过饱和浓度。 将体外结果与 PBPK 模型耦合提供了研究两种可能的吸收情况的机会，即有或没有实施沉淀。模拟结果表明，依曲韦林不沉淀的情况更能代表体内数据。在吸收后方面，血浆中依曲韦林未结合部分的浓度依赖性似乎对依曲韦林药代动力学具有显着影响。结论本研究强调了结合体外和计算机生物制药工具来提高我们在生物赋能制剂领域的知识的重要性。未来对其他生物赋能制剂的研究可用于进一步探索这种方法，以支持合理的制剂设计以及对临床结果的稳健预测。
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