A physiologically based biopharmaceutics modeling (PBBM) framework for characterizing formulation-dependent food effects: Paving the road towards fed state virtual BE studies for itraconazole amorphous solid dispersions
This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-speci...
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| Published in: | European journal of pharmaceutical sciences Vol. 209; p. 107047 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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Netherlands
Elsevier B.V
01.06.2025
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| ISSN: | 0928-0987, 1879-0720, 1879-0720 |
| Online Access: | Get full text |
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| Abstract | This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected to extensive in vitro biopharmaceutical testing, including solubility studies and dissolution tests under fasted and fed state conditions, revealing significant differences in dissolution behaviors between Sempera® and Tolsura®. The impact of food and hypochlorhydria on drug absorption was evaluated using a stepwise mechanistic deconvolution-reconvolution PBBM approach, integrating fundamental parameters based on the in vitro data into the final model. Our model not only successfully predicted the effects of acid reducing agents (ARA) and food on the oral absorption of ITRA, but also captured the between-subject variability, demonstrating the utility of this approach in understanding the complex interplay between drug, formulation, and gastrointestinal environment. Most importantly, the PBBM was able to accurately predict the positive impact of food on the absorption of Sempera® and the negative food effect of Tolsura®. The findings highlight the importance of considering formulation characteristics and gastrointestinal physiology, underscoring the potential of PBBM in bioequivalence (BE) assessment of generic formulations under varying physiological conditions, including in the fed state and in hypochlorhydric patients. The successful application of this stepwise and mechanistic PBBM approach suggests a potential pathway for streamlining drug development and may contribute to more informed decision-making for BE assessment.
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| AbstractList | This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected to extensive in vitro biopharmaceutical testing, including solubility studies and dissolution tests under fasted and fed state conditions, revealing significant differences in dissolution behaviors between Sempera® and Tolsura®. The impact of food and hypochlorhydria on drug absorption was evaluated using a stepwise mechanistic deconvolution-reconvolution PBBM approach, integrating fundamental parameters based on the in vitro data into the final model. Our model not only successfully predicted the effects of acid reducing agents (ARA) and food on the oral absorption of ITRA, but also captured the between-subject variability, demonstrating the utility of this approach in understanding the complex interplay between drug, formulation, and gastrointestinal environment. Most importantly, the PBBM was able to accurately predict the positive impact of food on the absorption of Sempera® and the negative food effect of Tolsura®. The findings highlight the importance of considering formulation characteristics and gastrointestinal physiology, underscoring the potential of PBBM in bioequivalence (BE) assessment of generic formulations under varying physiological conditions, including in the fed state and in hypochlorhydric patients. The successful application of this stepwise and mechanistic PBBM approach suggests a potential pathway for streamlining drug development and may contribute to more informed decision-making for BE assessment. This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected to extensive in vitro biopharmaceutical testing, including solubility studies and dissolution tests under fasted and fed state conditions, revealing significant differences in dissolution behaviors between Sempera® and Tolsura®. The impact of food and hypochlorhydria on drug absorption was evaluated using a stepwise mechanistic deconvolution-reconvolution PBBM approach, integrating fundamental parameters based on the in vitro data into the final model. Our model not only successfully predicted the effects of acid reducing agents (ARA) and food on the oral absorption of ITRA, but also captured the between-subject variability, demonstrating the utility of this approach in understanding the complex interplay between drug, formulation, and gastrointestinal environment. Most importantly, the PBBM was able to accurately predict the positive impact of food on the absorption of Sempera® and the negative food effect of Tolsura®. The findings highlight the importance of considering formulation characteristics and gastrointestinal physiology, underscoring the potential of PBBM in bioequivalence (BE) assessment of generic formulations under varying physiological conditions, including in the fed state and in hypochlorhydric patients. The successful application of this stepwise and mechanistic PBBM approach suggests a potential pathway for streamlining drug development and may contribute to more informed decision-making for BE assessment. [Display omitted] This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected to extensive in vitro biopharmaceutical testing, including solubility studies and dissolution tests under fasted and fed state conditions, revealing significant differences in dissolution behaviors between Sempera® and Tolsura®. The impact of food and hypochlorhydria on drug absorption was evaluated using a stepwise mechanistic deconvolution-reconvolution PBBM approach, integrating fundamental parameters based on the in vitro data into the final model. Our model not only successfully predicted the effects of acid reducing agents (ARA) and food on the oral absorption of ITRA, but also captured the between-subject variability, demonstrating the utility of this approach in understanding the complex interplay between drug, formulation, and gastrointestinal environment. Most importantly, the PBBM was able to accurately predict the positive impact of food on the absorption of Sempera® and the negative food effect of Tolsura®. The findings highlight the importance of considering formulation characteristics and gastrointestinal physiology, underscoring the potential of PBBM in bioequivalence (BE) assessment of generic formulations under varying physiological conditions, including in the fed state and in hypochlorhydric patients. The successful application of this stepwise and mechanistic PBBM approach suggests a potential pathway for streamlining drug development and may contribute to more informed decision-making for BE assessment.This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected to extensive in vitro biopharmaceutical testing, including solubility studies and dissolution tests under fasted and fed state conditions, revealing significant differences in dissolution behaviors between Sempera® and Tolsura®. The impact of food and hypochlorhydria on drug absorption was evaluated using a stepwise mechanistic deconvolution-reconvolution PBBM approach, integrating fundamental parameters based on the in vitro data into the final model. Our model not only successfully predicted the effects of acid reducing agents (ARA) and food on the oral absorption of ITRA, but also captured the between-subject variability, demonstrating the utility of this approach in understanding the complex interplay between drug, formulation, and gastrointestinal environment. Most importantly, the PBBM was able to accurately predict the positive impact of food on the absorption of Sempera® and the negative food effect of Tolsura®. The findings highlight the importance of considering formulation characteristics and gastrointestinal physiology, underscoring the potential of PBBM in bioequivalence (BE) assessment of generic formulations under varying physiological conditions, including in the fed state and in hypochlorhydric patients. The successful application of this stepwise and mechanistic PBBM approach suggests a potential pathway for streamlining drug development and may contribute to more informed decision-making for BE assessment. |
| ArticleNumber | 107047 |
| Author | Charbe, Nitin Shoyaib, Abdullah Al Pal, Arindom Polli, James Zhao, Liang Cristofoletti, Rodrigo Rudolph, Niklas Plano, David Boyce, Heather Dressman, Jennifer Wu, Fang |
| Author_xml | – sequence: 1 givenname: Niklas surname: Rudolph fullname: Rudolph, Niklas organization: Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany – sequence: 2 givenname: Nitin surname: Charbe fullname: Charbe, Nitin organization: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA – sequence: 3 givenname: David surname: Plano fullname: Plano, David organization: Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany – sequence: 4 givenname: Abdullah Al surname: Shoyaib fullname: Shoyaib, Abdullah Al organization: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA – sequence: 5 givenname: Arindom surname: Pal fullname: Pal, Arindom organization: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA – sequence: 6 givenname: Heather surname: Boyce fullname: Boyce, Heather organization: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA – sequence: 7 givenname: Liang surname: Zhao fullname: Zhao, Liang organization: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA – sequence: 8 givenname: Fang surname: Wu fullname: Wu, Fang organization: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA – sequence: 9 givenname: James surname: Polli fullname: Polli, James organization: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA – sequence: 10 givenname: Jennifer surname: Dressman fullname: Dressman, Jennifer email: Jennifer.Dressman@itmp.fraunhofer.de organization: Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany – sequence: 11 givenname: Rodrigo surname: Cristofoletti fullname: Cristofoletti, Rodrigo email: rcristofoletti@cop.ufl.edu organization: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/39983931$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1007_s11095_025_03866_8 crossref_primary_10_1016_j_ejps_2025_107129 crossref_primary_10_3390_pharmaceutics17040408 crossref_primary_10_3390_scipharm93030030 |
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| Keywords | In vitro biopharmaceutics assessment Food effect Hypochlorhydria Regulatory decision making PBBM Sempera Between-subject variability Itraconazole Tolsura Generic drug development |
| Language | English |
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| SubjectTerms | Administration, Oral Adult Antifungal Agents - administration & dosage Antifungal Agents - chemistry Antifungal Agents - pharmacokinetics Between-subject variability Biopharmaceutics - methods Chemistry, Pharmaceutical Drug Liberation Fasting Food effect Food-Drug Interactions Generic drug development Humans Hypochlorhydria In vitro biopharmaceutics assessment Intestinal Absorption Itraconazole Itraconazole - administration & dosage Itraconazole - chemistry Itraconazole - pharmacokinetics Male Models, Biological PBBM Regulatory decision making Sempera Solubility Tolsura |
| Title | A physiologically based biopharmaceutics modeling (PBBM) framework for characterizing formulation-dependent food effects: Paving the road towards fed state virtual BE studies for itraconazole amorphous solid dispersions |
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