PBPK Absorption Modeling: Establishing the In Vitro–In Vivo Link—Industry Perspective

Stillhart, Cordula; Pépin, Xavier; Tistaert, Christophe; Good, David; Bergh, An Van Den; Parrott, Neil; Kesisoglou, Filippos

doi:10.1208/s12248-019-0292-3

Cited by 64 publications

(49 citation statements)

References 30 publications

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“…The clinical evaluation of formulation variants that represent commercial formulation and processes to vary the most relevant CQAs to support PBBM can only be beneficial. If bioequivalence is demonstrated for the variants tested, in the absence of any modelling, the results can be used to define a clinical safe space where post-approval product changes can be managed (11). If variants show differences in vivo, PBBM can help interpolate the edge of failure of the safe space and help justify the proposed specifications (15).…”

Section: Discussionmentioning

confidence: 99%

“…To achieve CRDPS, regulators are strongly urging that methods have an in vivo link. This linkage, ideally, would be actual in vivo data in humans, as in the case of in vitro and in vivo correlations (IVIVC), or through modeling based on biopharmaceutical information (10,11). Modeling in addition to supporting the dissolution method and hence specifications, has other uses, as assisting in Quality by Design (QbD), bioequivalence (BE), and formulation development (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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The Case for Physiologically Based Biopharmaceutics Modelling (PBBM): What do Dissolution Scientists Need to Know?

Gray¹,

Mann²,

Barker³

et al. 2020

Dissolution Technol.

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The purpose of this article is to inform the dissolution scientist of a powerful emerging tool that provides in vivo linkage to dissolution methods. This tool is physiologically based biopharmaceutics modelling (PBBM). Dissolution scientists are mostly concerned with analytical sections of drug development, so exposure to modeling and other pharmacokinetics and biopharmaceutic concepts may be uncommon. PBBM is an in-silico model that focuses on the interactions between the in vivo physiology and the formulation and drug characteristics. The principles behind PBBM is that all mechanisms related to drug release, dissolution, and diffusion from the site of administration to the site of action can be described in a mechanistic way or semi-empirical way. The integration of in vitro dissolution data in PBBM is described, including examples of software and modeling applications. The expertise needed to use the software and appropriate training is discussed. The key inputs that are expected from the dissolution scientist include an understanding of the aqueous solubility across the physiological pH range, impact of in vivo relevant bile salts and phospholipids on solubilization, and the impact of surface pH on dissolution rate. An example of an advanced in vitro system, TNO intestinal model (TIM-1), will be discussed and its importance in establishing a biorelevant understanding of dissolution behavior. PBBM can evaluate the clinical relevance of a dissolution method and justify specifications and ultimately provide an approval advantage to the sponsor. A well-supported dissolution method that provides clinically relevant drug product specifications (CRDPS) will be viewed with favor by the regulators. Therefore, the partnering of a dissolution scientist and biopharmaceutics scientist to develop PBBM is clearly an important step forward in drug development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Case for Physiologically Based Biopharmaceutics Modelling (PBBM): What do Dissolution Scientists Need to Know?

Gray¹,

Mann²,

Barker³

et al. 2020

Dissolution Technol.

View full text Add to dashboard Cite

show abstract

“…Readers are referred to those articles for a more in-depth discussion of the current landscape as well as specific recent examples. [4][5][6][7] In the last decade, a sizable number of publications have also reported application of PBPK/PBBM models to food effect prediction or food effect characterization. Table 1 summarizes those publications that include model comparison/validation against clinical data.…”

Section: Progress Over the Years And Current Status Of Pbpk Modeling mentioning

confidence: 99%

Can PBPK Modeling Streamline Food Effect Assessments?

Kesisoglou

2020

The Journal of Clinical Pharma

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Physiologically based pharmacokinetic (PBPK) modeling is routinely used to study drug-drug interactions, replace some dedicated clinical studies, and inform product labeling. More recently, there has been increased application of PBPK models in the oral absorption field around drug product quality. Given the success of the models to characterize absorption of several orally administered drug products, a question arises whether PBPK could be used in a clinical setting to model food-drug interactions and thus streamline food effect assessments. Multiple publications have reported food effect predictions and comparisons with clinical data, primarily focusing on 2 food effect mechanisms: slowing down of gastric emptying and luminal solubilization by bile salts. Based on the available literature, this commentary proposes a workflow that PBPK model could be used to streamline food effect assessment during clinical development for different Biopharmaceutics Classification System classes.

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“…In addition, because PBPK modeling is a probabilistic approach by nature, population simulations may allow better assessment of models performance, particularly when highly variable outcomes measured in small clinical trials are used for benchmarking. [3][4][5][6] A typical workflow applied in IVIVEs starts by modeling the in vitro predictive dissolution data to obtain relevant parameters that are then inputted into the PBPK model to predict systemic drug exposure. The empirical equation described by a Weibull or an empirical firstorder model have been successfully used to, respectively, describe experimental dissolution data and estimate precipitation parameters from transfer experiments.…”

Section: Introductionmentioning

confidence: 99%

Integrating Drug- and Formulation-Related Properties With Gastrointestinal Tract Variability Using a Product-Specific Particle Size Approach: Case Example Ibuprofen

Cristofoletti

Hens

Patel

et al. 2019

Journal of Pharmaceutical Sciences

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Keywords:absorption dissolution physiologically based pharmacokinetic (PBPK) modeling in vitro-in vivo (IVIVC) correlation(s) mechanistic modeling particle size a b s t r a c tIn the present study, an in vitroein vivo extrapolation of dissolution integrated to a physiologically based pharmacokinetics modeling approach, considering a product-specific particle size distribution and a selfbuffering effect of the drug, is introduced and appears to be a promising translational modeling strategy to support drug product development, manufacturing changes and setting clinically relevant specifications for immediate release formulations containing ibuprofen and other weak acids with similar properties.

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PBPK Absorption Modeling: Establishing the In Vitro–In Vivo Link—Industry Perspective

Cited by 64 publications

References 30 publications

The Case for Physiologically Based Biopharmaceutics Modelling (PBBM): What do Dissolution Scientists Need to Know?

The Case for Physiologically Based Biopharmaceutics Modelling (PBBM): What do Dissolution Scientists Need to Know?

Can PBPK Modeling Streamline Food Effect Assessments?

Integrating Drug- and Formulation-Related Properties With Gastrointestinal Tract Variability Using a Product-Specific Particle Size Approach: Case Example Ibuprofen

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