<i>In vitro</i> methods to assess drug precipitation in the fasted small intestine – a PEARRL review

O’Dwyer, P. J.; Litou, Chara; Box, Karl; Dressman, Jennifer B.; Kostewicz, Edmund; Kuentz, Martin; Reppas, Christos

doi:10.1111/jphp.12951

Cited by 52 publications

(31 citation statements)

References 105 publications

(136 reference statements)

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“…However, due to the increased pH in the small intestine, concentrations (especially of lipophilic weak bases) arriving in the small intestine could supersaturate and/or precipitate in the contents of the small intestine and accordingly impact (at least early) drug exposure. Many in vitro methodologies have been proposed in an attempt to better evaluate this dynamic in vivo dissolution process [1].…”

Section: Introductionmentioning

confidence: 99%

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On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

et al. 2020

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A small-scale biphasic dissolution setup and a small-scale dissolution-permeation (D-P) setup were evaluated for their usefulness in simulating the luminal precipitation of three lipophilic weak bases-dipyridamole, ketoconazole and itraconazole. The transition from the gastric to intestinal environment was incorporated into both experimental procedures. Emulsification during the biphasic dissolution experiments had a minimal impact on the data, when appropriate risk mitigation steps were incorporated. Precipitation parameters estimated from the in vitro data were inputted into the Simcyp ® physiologically based pharmacokinetic (PBPK) modelling software and simulated human plasma profiles were compared with previously published pharmacokinetic data. Average C max and AUC values estimated using experimentally derived precipitation parameters from the biphasic experiments deviated from corresponding published actual values less than values estimated using the default simulator parameters for precipitation. The slow rate of transport through the biomimetic membrane in the D-P setup limited its usefulness in forecasting the rates of in vivo precipitation used in the modelling of average plasma profiles.

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Section: Introductionmentioning

confidence: 99%

“…Another issue with many of the in vitro methodologies is the lack of simulation of drug disappearance from bulk luminal contents, due to the absorption process. As a result, in many situations, overestimation of precipitation has been reported [1].…”

Section: Introductionmentioning

confidence: 99%

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

et al. 2020

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“…As a biorelevant system, it is essential to expose drug products to different environments in the GI tract, to those in the stomach first, and then to those in the small intestine. Multiple compartmental GI transfer systems reproduced these processes by connecting several vessels filled with biorelevant fluids [ 4 , 6 , 7 , 8 , 9 , 10 , 12 , 13 ]. Small particles or dissolved drugs in the fluids were transferred from one vessel to the next using a peristatic pump to mimic a GI transit in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the less biorelevant conditions that are currently used in in vitro drug dissolution tests defined by the Pharmacopeia in each country (typically a paddle or a basket in 900 mL vessels), various kinds of in vivo predictive in vitro methods for investigating drug dissolution in the GI tract have been developed. Several types of multiple compartmental GI transfer systems have been developed so far, in which two or three dissolution vessels are connected by peristatic pumps for analyzing the drug dissolution in each part of the GI tract [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. As one of those systems, a multicompartmental in vitro dissolution apparatus, the gastrointestinal simulator (GIS), was shown to be able to detect the effect of gastric pH on the dissolution profile of dipyridamole, a BCS class II weak base drug, which corresponded well to the clinically observed drug–drug interaction with famotidine [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Bioequivalence of Oral Drug Products in the Healthy and Special Populations: Assessment and Prediction Using a Newly Developed In Vitro System “BE Checker”

et al. 2021

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In order to assess and predict the bioequivalence (BE) of oral drug products, a new in vitro system “BE checker” was developed, which reproduced the environmental changes in the gastrointestinal (GI) tract by changing the pH, composition, and volume of the medium in a single chamber. The dissolution and membrane permeation profiles of drugs from marketed products were observed in the BE checker under various conditions reflecting the inter-patient variations of the GI physiology. As variable factors, initial gastric pH, gastric emptying time, and GI agitation strength were varied in vitro. Dipyridamole, a basic drug, showed rapid and supersaturated dissolution when the paddle speed in the donor chamber was 200 rpm, which corresponds to the high agitation strength in the stomach. In contrast, supersaturated dissolution disappeared, and the permeated amount decreased under the conditions with a slow paddle speed (100 and 50 rpm) and short gastric emptying time (10 min). In those conditions, disintegration of the formulation was delayed, and the subsequent dissolution of dipyridamole was not completed before the fluid pH was changed to neutral. Similar results were obtained when the initial gastric pH was increased to 3.0, 5.0, and 6.5. To investigate that those factors also affect the BE of oral drug products, dissolution and permeation of naftopidil from its ordinary and orally disintegrating (OD) tablets were observed in the BE checker. Both products showed the similar dissolution profiles when the paddle speed and gastric emptying time were set to 100 rpm and 10 or 20 min, respectively. However, at a low paddle speed (50 rpm), the dissolution of naftopidil from ordinary tablets was slower than that from the OD tablets, and the permeation profiles became dissimilar. These results indicated the possibility of the bioinequivalence of some oral formulations in special patients whose GI physiologies are different from those in the healthy subjects. The BE checker can be a highly capable in vitro tool to assess the BE of oral drug products in various populations.

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“…In the last decade, multiple in vitro and in silico models have been optimized and validated across different biopharmaceutics projects to facilitate oral drug product development. [10][11][12] There is a need to develop more predictive in vitro dissolution models to streamline data input from these biorelevant in vitro devices into physiologically based pharmacokinetic (PBPK) models (i.e., bottom-up approach). 13 PBPK models describe the factors influencing the absorption, distribution, metabolism, and elimination processes resulting in simulated drug concentration-time profiles in a human tissue of interest.…”

Section: Introductionmentioning

confidence: 99%

Application of a Dynamic Fluid and pH Model to Simulate Intraluminal and Systemic Concentrations of a Weak Base in GastroPlus™

Hens

Bolger

2019

Journal of Pharmaceutical Sciences

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The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are biorelevant and are sensitive to changes in parameter values. Human gastrointestinal physiology involves many processes that change as a function of time. In this work, a dynamic fluid and pH model was applied in GastroPlus ™ to simulate intraluminal and systemic concentrations of the weak base posaconazole in a biorelevant manner. Simulated results were compared with observed data, extracted from a previously reported human in vivo gastrointestinal aspiration study. Three different formulations were explored (i.e., 1 solution [20 mg dose strength] and 2 suspensions [both 40 mg dose strength]). Simulated results were compared and in line with the observed results for different intraluminal (e.g., precipitated fraction) and systemic parameters (e.g., plasma C max). The optimization of the advanced compartmental and absorption transit model related to fluid dynamics and dynamic pH in this work creates perspectives to validate this model with other reference data derived from aspiration/magnetic resonance imaging studies.

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In vitro methods to assess drug precipitation in the fasted small intestine – a PEARRL review

Cited by 52 publications

References 105 publications

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

Bioequivalence of Oral Drug Products in the Healthy and Special Populations: Assessment and Prediction Using a Newly Developed In Vitro System “BE Checker”

Application of a Dynamic Fluid and pH Model to Simulate Intraluminal and Systemic Concentrations of a Weak Base in GastroPlus™

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