Deciphering nifedipine in vivo delivery from modified release dosage forms: Identification of food effect

Abstract With the increased reliance on in vitro dissolution testing as an indicator of in vivo drug behavior and the trend towards the in silico modeling of dosage form performance, the need for bioperformance dissolution methodology development has been enhanced. Determination of the in vivo drug delivery profile is essential for the bioperformance dissolution test development and in vitro/in vivo correlation modeling, as well as the understanding of absorption mechanisms. The aim of this study was to compare different methods in terms of their usefulness and applicability in deciphering in vivo delivery of nifedipine administered in modified release dosage forms. A detailed survey of publications on nifedipine pharmacokinetics was done and used to identify the magnitude of food effect. In vitro dissolution testing was performed under various experimental conditions. Obtained results indicate the potential for using the developed in silico model coupled with discriminative in vitro dissolution data for identification of the in vivo drug product behavior

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Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/jpps32260 ◽

2021 ◽

Vol 24 ◽

pp. 548-562

Author(s):

Matthias Shona Roost ◽

Henrike Potthast ◽

Chantal Walther ◽

Alfredo García-Arieta ◽

Ivana Abalos ◽

...

Keyword(s):

Immediate Release ◽

Dosage Forms ◽

Oral Dosage ◽

In Vitro Dissolution ◽

Quantitative Composition ◽

Modified Release ◽

Solid Oral Dosage Forms ◽

Oral Dosage Forms

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.

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Prediction of in-vivo pharmacokinetic profile for immediate and modified release oral dosage forms of furosemide using an in-vitro-in-silico-in-vivo approach

Journal of Pharmacy and Pharmacology ◽

10.1111/jphp.12365 ◽

2015 ◽

Vol 67 (5) ◽

pp. 651-665 ◽

Cited By ~ 12

Author(s):

Keiichi Otsuka ◽

Christian Wagner ◽

Arzu Selen ◽

Jennifer Dressman

Keyword(s):

In Silico ◽

Pharmacokinetic Profile ◽

Dosage Forms ◽

Oral Dosage ◽

Modified Release ◽

Oral Dosage Forms

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Predicting in vivo absorption behavior of oral modified release dosage forms containing pH-dependent poorly soluble drugs using a novel pH-adjusted biphasic in vitro dissolution test

European Journal of Pharmaceutics and Biopharmaceutics ◽

10.1016/j.ejpb.2010.05.006 ◽

2010 ◽

Vol 76 (1) ◽

pp. 105-111 ◽

Cited By ~ 47

Author(s):

Ulrich Heigoldt ◽

Florian Sommer ◽

Rolf Daniels ◽

Karl-Gerhard Wagner

Keyword(s):

Dosage Forms ◽

In Vitro Dissolution ◽

Dissolution Test ◽

Poorly Soluble Drugs ◽

Modified Release ◽

In Vivo Absorption ◽

Poorly Soluble ◽

Ph Dependent

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A Mechanistic Physiologically-Based Biopharmaceutics Modeling (PBBM) Approach to Assess the In Vivo Performance of an Orally Administered Drug Product: From IVIVC to IVIVP

Pharmaceutics ◽

10.3390/pharmaceutics12010074 ◽

2020 ◽

Vol 12 (1) ◽

pp. 74 ◽

Cited By ~ 8

Author(s):

Marival Bermejo ◽

Bart Hens ◽

Joseph Dickens ◽

Deanna Mudie ◽

Paulo Paixão ◽

...

Keyword(s):

Oral Absorption ◽

Drug Product ◽

Continuous Optimization ◽

In Vitro Dissolution ◽

Oral Drug ◽

Dissolution Testing ◽

Bicarbonate Buffer ◽

Physiologically Based

The application of in silico modeling to predict the in vivo outcome of an oral drug product is gaining a lot of interest. Fully relying on these models as a surrogate tool requires continuous optimization and validation. To do so, intraluminal and systemic data are desirable to judge the predicted outcomes. The aim of this study was to predict the systemic concentrations of ibuprofen after oral administration of an 800 mg immediate-release (IR) tablet to healthy subjects in fasted-state conditions. A mechanistic oral absorption model coupled with a two-compartmental pharmacokinetic (PK) model was built in Phoenix WinNonlinWinNonlin® software and in the GastroPlus™ simulator. It should be noted that all simulations were performed in an ideal framework as we were in possession of a plethora of in vivo data (e.g., motility, pH, luminal and systemic concentrations) in order to evaluate and optimize these models. All this work refers to the fact that important, yet crucial, gastrointestinal (GI) variables should be integrated into biopredictive dissolution testing (low buffer capacity media, considering phosphate versus bicarbonate buffer, hydrodynamics) to account for a valuable input for physiologically-based pharmacokinetic (PBPK) platform programs. While simulations can be performed and mechanistic insights can be gained from such simulations from current software, we need to move from correlations to predictions (IVIVC → IVIVP) and, moreover, we need to further determine the dynamics of the GI variables controlling the dosage form transit, disintegration, dissolution, absorption and metabolism along the human GI tract. Establishing the link between biopredictive in vitro dissolution testing and mechanistic oral absorption modeling (i.e., physiologically-based biopharmaceutics modeling (PBBM)) creates an opportunity to potentially request biowaivers in the near future for orally administered drug products, regardless of its classification according to the Biopharmaceutics Classification System (BCS).

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