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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Vydáno v:European journal of pharmaceutical sciences Ročník 209; s. 107047
Hlavní autoři: Rudolph, Niklas, Charbe, Nitin, Plano, David, Shoyaib, Abdullah Al, Pal, Arindom, Boyce, Heather, Zhao, Liang, Wu, Fang, Polli, James, Dressman, Jennifer, Cristofoletti, Rodrigo
Médium: Journal Article
Jazyk:angličtina
Vydáno: Netherlands Elsevier B.V 01.06.2025
Témata:
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
In vitro biopharmaceutics assessment
Food effect
Hypochlorhydria
Regulatory decision making
PBBM
Sempera
Between-subject variability
Itraconazole
Tolsura
Generic drug development
ISSN:0928-0987, 1879-0720, 1879-0720
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Shrnutí: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]
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0928-0987
1879-0720
1879-0720
DOI:10.1016/j.ejps.2025.107047