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Development of In Vitro Dissolution Testing Methods to Simulate Fed Conditions for Immediate Release Solid Oral Dosage Forms

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Abstract

In vitro dissolution testing is widely used to mimic and predict in vivo performance of oral drug products in the gastrointestinal (GI) tract. This literature review assesses the current in vitro dissolution methodologies being employed to simulate and predict in vivo drug dissolution under fasted and fed conditions, with emphasis on immediate release (IR) solid oral dosage forms. Notable human GI physiological conditions under fasted and fed states have been reviewed and summarized. Literature results showed that dissolution media, mechanical forces, and transit times are key dissolution test parameters for simulating specific postprandial conditions. A number of biorelevant systems, including the fed stomach model (FSM), GastroDuo device, dynamic gastric model (DGM), simulated gastrointestinal tract models (TIM), and the human gastric simulator (HGS), have been developed to mimic the postprandial state of the stomach. While these models have assisted in expanding physiological relevance of in vitro dissolution tests, in general, these models lack the ability to fully replicate physiological conditions/processes. Furthermore, the translatability of in vitro data to an in vivo system remains challenging. Additionally, physiologically based pharmacokinetic (PBPK) modeling has been employed to evaluate the effect of food on drug bioavailability and bioequivalence. Here, we assess the current status of in vitro dissolution methodologies and absorption PBPK modeling approaches to identify knowledge gaps and facilitate further development of in vitro dissolution methods that factor in fasted and fed states. Prediction of in vivo drug performance under fasted and fed conditions via in vitro dissolution testing and modeling may potentially help efforts in harmonizing global regulatory recommendations regarding in vivo fasted and fed bioequivalence studies for solid oral IR products.

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Funding

Dr. Timothy R. Lex was supported in part by an appointment to the Research Participation Program at the CDER, US Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and FDA.

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Authors and Affiliations

  1. Division of Complex Drug Analysis, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, St. Louis, Missouri, 63110, USA

    Timothy R. Lex, Jason D. Rodriguez & Zongming Gao

  2. Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Lei Zhang & Wenlei Jiang

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  1. Timothy R. Lex
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Contributions

Dr. Timothy R. Lex was involved in methodology, data analyses, interpretation, writing, reviewing, and editing of the manuscript. Dr. Zongming Gao and Dr. Wenlei Jiang were involved in conceptualization, methodology, data analyses, interpretation, writing, reviewing, and editing of the manuscript. Dr. Jason Rodriguez and Dr. Lei Zhang were involved in reviewing and editing of the manuscript.

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Correspondence to Wenlei Jiang or Zongming Gao.

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This review reflects the views of the authors and should not be construed to represent FDA’s views or policies. This project was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and US FDA.

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Lex, T.R., Rodriguez, J.D., Zhang, L. et al. Development of In Vitro Dissolution Testing Methods to Simulate Fed Conditions for Immediate Release Solid Oral Dosage Forms. AAPS J 24, 40 (2022). https://doi.org/10.1208/s12248-022-00690-5

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