In Vivo Predictive Dissolution (IPD) for Carbamazepine Formulations: Additional Evidence Regarding a Biopredictive Dissolution Medium

Bermejo, Marival; Meulman, Jessica; Davanço, Marcelo Gomes; Carvalho, Patrícia de Oliveira; González‐Álvarez, Isabel; Campos, Daniel Rossi de

doi:10.3390/pharmaceutics12060558

Cited by 8 publications

(4 citation statements)

References 31 publications

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“…In this study, the in vitro drug dissolution in the GIS is predicted using a mass transport model. The total dose dissolved in stomach, duodenum, and jejunum compartments over 2 h was calculated for palbociclib under high-gastric pH conditions mentioned in the In Vitro Dissolution Prediction Model . The drug in vivo fraction absorbed was calculated using the Wagner–Nelson one-compartmental model from the plasma concentration profile of patients taking palbociclib with PPIs. ,, The in vitro drug dissolution prediction under high gastric pH is correlated with the in vivo fraction absorbed with drug co-administration under PPI conditions.…”

Section: Methodsmentioning

confidence: 99%

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

et al. 2021

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Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract’s physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. et al. Mol. Pharm. 2018 and Bermejo, et al. M. Mol. Pharm. 2018). The dissolution of an ionizable drug may benefit from manipulating in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds’ dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties (e.g., solubility and pK a) and its interplay with the pH modifier pK a or pK as. As an example of this complex interaction, for basic drugs with high pK a and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as pK a, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to in vitro multi-compartment dissolution vessels and are validated by in vitro experiments in the gastrointestinal simulator. This model’s predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both in vitro and in vivo conditions.

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Section: Methodsmentioning

confidence: 99%

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

et al. 2021

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“…In the future, the IVIVS approach can be expanded by adding more pharmacokinetic models, coupling it with biopredictive media, simulated in vitro models, and formulation predictive studies [ 4 , 14 , 76 , 77 ]. Using the appropriate in vitro data (with adequate discriminatory ability), even predictions for the comparative pharmacological effect can be made, by using joint in vitro—pharmacokinetic—pharmacodynamic simulations.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, in the recent years the development of biorelevant media, as input into physiologically based absorption modeling, has been proved a useful tool for the prediction of in vivo performance [ 12 , 13 ]. In the same vein, biopredictive media have been assessed in conjunction with IVIVC approaches [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

An In Vitro–In Vivo Simulation Approach for the Prediction of Bioequivalence

Vlachou

Karalis

2021

Materials

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The aim of this study was to develop a new in vitro–in vivo simulation (IVIVS) approach in order to predict the outcome of a bioequivalence study. The predictability of the IVIVS procedure was evaluated through its application in the development process of a new generic product of amlodipine/irbesartan/hydrochlorothiazide. The developed IVIVS methodology is composed of three parts: (a) mathematical description of in vitro dissolution profiles, (b) mathematical description of in vivo kinetics, and (c) development of joint in vitro–in vivo simulations. The entire programming was done in MATLAB® and all created scripts were validated through other software. The IVIVS approach can be implemented for any number of subjects, clinical design, variability and can be repeated for thousands of times using Monte Carlo techniques. The probability of success of each scenario is recorded and finally, an overall assessment is made in order to select the most suitable batch. Alternatively, if the IVIVS shows reduced probability of BE success, the R&D department is advised to reformulate the product. In this study, the IVIVS approach predicted successfully the BE outcome of the three drugs. During the development of generics, the IVIVS approach can save time and expenses.

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“…In vitro dissolution testing is generally accepted as the most important test for dosage form characterization, which is used in different phases of the product life-cycle, starting from the early development stages, through product optimization, including stability assessment, technology transfer, routine quality control and post-approval changes justification. Within the integrated biopharmaceutical approach in pharmaceutical development and drug characterization, dissolution testing is expected to serve as a substitute for in vivo testing, and the focus is placed on the discriminatory in vivo predictive dissolution test development and establishment of clinically relevant dissolution specifications [10][11][12]. While the most often used dissolution equipment for oral dosage form characterization includes compendial rotating paddle/rotating basket apparatus, extensive research efforts are directed towards design of dynamic apparatus which would more closely mimic hydrodynamics and transit times encountered in vivo, including the use of complex media, which simulate composition of physiological fluids in different parts of the gastrointestinal tract [13][14][15][16].…”

Section: In Vivo Predictive Dissolution Testingmentioning

confidence: 99%

Integrated biopharmaceutical approach in pharmaceutical development and drug characterization: General concept and application

Cvijic

Ibric

Parojcic

2020

Hem Ind

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The importance of biopharmaceutical considerations in pharmaceutical development and drug characterization has been well recognized both by pharmaceutical industry and regulatory authorities as a tool to establish predictive relationships between drug product quality attributes (in vitro data) and its clinical performance (in vivo data). In the present paper, contemporary biopharmaceutics toolkit including in vivo predictive dissolution testing, Biopharmaceutics Classification System, physiologically based pharmacokinetic and biopharmaceutics modeling and simulation, in vitro-in vivo correlation and biowaiver, are reviewed with regards to relevant general principles and applicability. The recently introduced innovative strategy for patient-centric drug development using an integrated systems approach grounded in fundamental biopharmaceutics concepts, clinical insights and therapeutic drug delivery targets, described as Biopharmaceutics Risk Assessment Roadmap (BioRAM) is also presented. Further development in the field will benefit from joint efforts and exchange of knowledge and experiences between pharmaceutical industry and regulatory authorities for the common goal to accelerate development of effective and safe drug products designed in accordance with patients? needs and expectations.

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In Vivo Predictive Dissolution (IPD) for Carbamazepine Formulations: Additional Evidence Regarding a Biopredictive Dissolution Medium

Cited by 8 publications

References 31 publications

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

An In Vitro–In Vivo Simulation Approach for the Prediction of Bioequivalence

Integrated biopharmaceutical approach in pharmaceutical development and drug characterization: General concept and application

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