Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 11176

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Guest Editor
Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal
Interests: bioavailability; bioequivalence; physiological-based biopharmaceutical models; population pharmacokinetics; modelling and simulation; artificial intelligence
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Special Issue Information

Dear Colleague,

Systemic absorption is often incomplete when given extravascularly. This may be due to formulation issues, drug’s physicochemical characteristics influencing solubilization and membrane permeability, affinity to carrier-mediated transport systems, and chemical and metabolic stability, just to name a few. Knowing the extent of absorption, in a Bioavailability study, is fundamental to define the correct extravascular dose. Comparing the fraction absorbed from different extravascular dosage forms or routes, in a relative bioavailability study, is an alternative approach when intravenous data are not available. Finally, ensuring a similar rate and extent of absorption in Bioequivalence testing is a way to extrapolate the therapeutic outcome between two pharmaceutical drug products. In the past, most of these issues were assessed by in vivo studies, mostly after single dose administration, comparing pharmacokinetic exposure parameters (Cmax and AUC). More complex drug products are, nowadays, requiring additional attention and more complex clinical designs. Further, more and more, additional computational tools are available, such as physiologically based biopharmaceutical models or population pharmacokinetic approaches, frequently connected to in vitro–in vivo correlations that may foster drug discovery and development.

In this Special Issue on Drug Product Performance, we will focus on new tools and approaches for establishing systemic bioavailability and bioequivalence, and will include in silico, in vitro and in vivo methods. We invite researchers, drug developers and regulators to submit their original research or review articles with expert opinions and perspectives in this area.

Dr. Paulo Paixão
Guest Editor

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Keywords

  • bioavailability
  • relative bioavailability
  • bioequivalence
  • biowaivers
  • statistical issues
  • regulatory issues
  • in vitro–in vivo correlations
  • physiologically based biopharmaceutical models
  • physiologically based pharmacokinetic models
  • qualification of models
  • population pharmacokinetic models
  • biopharmaceutical classification system
  • in vitro dissolution
  • dissolution metrics
  • predictive dissolution
  • clinical trial simulations
  • clinical trial optimization
  • healthy subjects in BA/BE trials
  • patients in BA/BE trials
  • pharmacokinetic parameters for BA/BE assessment
  • narrow therapeutic index drugs
  • highly variable drug products
  • immediate-release formulations
  • modified-release formulations
  • multiphasic drug products
  • extravascular routes of administration

Published Papers (7 papers)

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Research

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14 pages, 1851 KiB  
Article
In Vivo Predictive Dissolution and Biopharmaceutic-Based In Silico Model to Explain Bioequivalence Results of Valsartan, a Biopharmaceutics Classification System Class IV Drug
by Isabel Gonzalez-Alvarez, Alejandro Ruiz-Picazo, Ruben Selles-Talavera, Andres Figueroa-Campos, Virginia Merino, Marival Bermejo and Marta Gonzalez-Alvarez
Pharmaceutics 2024, 16(3), 390; https://doi.org/10.3390/pharmaceutics16030390 - 13 Mar 2024
Viewed by 649
Abstract
The purpose of this study was to predict the in vivo bioequivalence (BE) outcome of valsartan (VALS, BCS class IV) from three oral-fixed combination products with hydrochlorothiazide (HCTZ, BCS class III) (Co-Diovan® Forte as reference and two generic formulations in development) [...] Read more.
The purpose of this study was to predict the in vivo bioequivalence (BE) outcome of valsartan (VALS, BCS class IV) from three oral-fixed combination products with hydrochlorothiazide (HCTZ, BCS class III) (Co-Diovan® Forte as reference and two generic formulations in development) by conducting in vivo predictive dissolution with a gastrointestinal simulator (GIS) and a physiologically based biopharmaceutic model (PBBM). In the first BE study, the HCTZ failed, but the VALS 90% CI of Cmax and the AUC were within the acceptance limits, while, in the second BE study, the HCTZ 90% CI of Cmax and the AUC were within the acceptance limits, but the VALS failed. As both drugs belong to different BCS classes, their limiting factors for absorption are different. On the other hand, the gastrointestinal variables affected by the formulation excipients have a distinct impact on their in vivo exposures. Dissolution tests of the three products were performed in a GIS, and a PBBM was constructed for VALS by incorporating in the mathematical model of the in vitro–in vivo correlation (IVIVC) the gastrointestinal variables affected by the excipients, namely, VALS permeability and GI transit time. VALS permeability in presence of the formulation excipients was characterized using the in situ perfusion method in rats, and the impact of the excipients on the GI transit times was estimated from the HCTZ’s in vivo results. The model was able to fit the in vivo BE results with a good prediction error. This study contributes to the field by showing the usefulness of PBBM in establishing in vitro–in vivo relationships incorporating not only dissolution data but also other gastrointestinal critical variables that affect drug exposure in BCS class IV compounds. Full article
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14 pages, 1003 KiB  
Article
Effect of the Similarity of Formulations and Excipients of Approved Generic Drug Products on In Vivo Bioequivalence for Putative Biopharmaceutics Classification System Class III Drugs
by Ping Ren, Theresa Chan, Wen-Cheng Yang, Mitchell Frost, Yan Wang, Markham Luke, Myong-Jin Kim, Robert Lionberger and Yi Zhang
Pharmaceutics 2023, 15(9), 2366; https://doi.org/10.3390/pharmaceutics15092366 - 21 Sep 2023
Viewed by 1504
Abstract
One of the potential essential factors that restricts generic industry from applying the Biopharmaceutics Classification System (BCS) Class III biowaiver is adherence to the stringent formulation criteria for formulation qualitative (Q1) sameness and quantitative (Q2) similarity. The present study has investigated formulations and [...] Read more.
One of the potential essential factors that restricts generic industry from applying the Biopharmaceutics Classification System (BCS) Class III biowaiver is adherence to the stringent formulation criteria for formulation qualitative (Q1) sameness and quantitative (Q2) similarity. The present study has investigated formulations and excipients from 16 putative BCS Class III drug substances in a total of 19 drug products via 133 approved abbreviated new drug applications (ANDAs) containing in vivo bioequivalence (BE) studies in human subjects during the time period from 2006 to 2022. We included the BCS Class III drugs in this study by referring to published literature, the World Health Organization (WHO) BCS Class I-IV list, FDA internal assessments, and physicochemical properties (high solubility and low permeability) of specific drug substances. Based upon all 133 approved generic formulations in this study, the highest amount of each different compendial excipient with a total of 40 is defined as its corresponding typical amount that has not shown any potential impact on in vivo drug absorption. In the present study, although only 30.08% of the investigated generic formulations met Q1 the same/Q2 similar formulation criteria for the BCS Class III biowaiver, and while approximately 69.92% failed to meet those criteria with non-Q1/Q2 similar formulations, all test/reference ratios (T/R) and 90% confidence intervals for all instrumental PK parameters (AUC0-t, AUC0-inf, and Cmax) met the bioequivalence (BE) criteria (80–125%). The results of formulation assessment suggest that the commonly used excipients without atypical amounts did not impact absorption of 16 putative BCS Class III drug substances. The rate and extent of absorption of drugs appears to be more dependent upon the biopharmaceutic and physiochemical properties of BCS Class III drug substance and less, or not dependent upon their formulations, excipients, and the excipients class. Our findings may lead to a more flexible formulation design space regarding the stringent BCS Class III formulation criteria. Full article
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18 pages, 5473 KiB  
Article
Understanding Discordance between In Vitro Dissolution, Local Gut and Systemic Bioequivalence of Budesonide in Healthy and Crohn’s Disease Patients through PBPK Modeling
by Chunyan Han, Tiancheng Sun, Siri Kalyan Chirumamilla, Frederic Y. Bois, Mandy Xu and Amin Rostami-Hodjegan
Pharmaceutics 2023, 15(9), 2237; https://doi.org/10.3390/pharmaceutics15092237 - 30 Aug 2023
Viewed by 1273
Abstract
The most common method for establishing bioequivalence (BE) is to demonstrate similarity of concentration–time profiles in the systemic circulation, as a surrogate to the site of action. However, similarity of profiles from two formulations in the systemic circulation does not imply similarity in [...] Read more.
The most common method for establishing bioequivalence (BE) is to demonstrate similarity of concentration–time profiles in the systemic circulation, as a surrogate to the site of action. However, similarity of profiles from two formulations in the systemic circulation does not imply similarity in the gastrointestinal tract (GIT) nor local BE. We have explored the concordance of BE conclusions for a set of hypothetical formulations based on budesonide concentration profiles in various segments of gut vs. those in systemic circulation using virtual trials powered by physiologically based pharmacokinetic (PBPK) models. The impact of Crohn’s disease on the BE conclusions was explored by changing physiological and biological GIT attributes. Substantial ‘discordance’ between local and systemic outcomes of VBE was observed. Upper GIT segments were much more sensitive to formulation changes than systemic circulation, where the latter led to false conclusions for BE. The ileum and colon showed a lower frequency of discordance. In the case of Crohn’s disease, a product-specific similarity factor might be needed for products such as Entocort® EC to ensure local BE. Our results are specific to budesonide, but we demonstrate potential discordances between the local gut vs. systemic BE for the first time. Full article
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21 pages, 1139 KiB  
Article
Discriminative Dissolution Method Using the Open-Loop Configuration of the USP IV Apparatus to Compare Dissolution Profiles of Metoprolol Tartrate Immediate-Release Tablets: Use of Kinetic Parameters
by Bruno Solis-Cruz, Daniel Hernandez-Patlan, Elvia A. Morales Hipólito, Guillermo Tellez-Isaias, Alejandro Alcántara Pineda and Raquel López-Arellano
Pharmaceutics 2023, 15(9), 2191; https://doi.org/10.3390/pharmaceutics15092191 - 24 Aug 2023
Cited by 1 | Viewed by 1078
Abstract
The use of the USP IV apparatus (flow-through cell) has gained acceptance in recent years due to its versatility and ability to discriminate due to its hydrodynamic conditions. Therefore, the objective of the present study was to develop a discriminative dissolution method in [...] Read more.
The use of the USP IV apparatus (flow-through cell) has gained acceptance in recent years due to its versatility and ability to discriminate due to its hydrodynamic conditions. Therefore, the objective of the present study was to develop a discriminative dissolution method in the USP IV apparatus using the open-loop configuration, as well as to propose a method to compare non-cumulative dissolution profiles obtained in the open-loop configuration considering kinetic parameters and validate its predictive power through its comparison with independent and dependent methods using five commercial immediate-release tablet drugs (one reference drug and four generic drugs) of metoprolol tartrate as a model drug. The comparison of the non-accumulated dissolution profiles consisted of determining the geometric ratio of Cmax, AUC0, AUC0Cmax, and Tmax (kinetic parameters) of the generic/reference drugs, whereby generic drugs “C” and “D” presented the highest probability of similarity since their 90% confidence intervals were included, or they were very close to the acceptance interval (80.00–125.00%). These results were consistent with the f2, bootstrap f2, and dissolution efficiency approaches (independent models). In conclusion, the proposed comparison method can be an important tool to establish similarity in dissolution profiles and to facilitate the development/selection of new formulations and positively ensure bioequivalence in clinical studies. Full article
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12 pages, 1011 KiB  
Article
Relationship between Pharmacokinetic Profile and Clinical Efficacy Data of Three Different Forms of Locally Applied Flurbiprofen in the Mouth/Throat
by Vit Perlik, Anuradha Kulasekaran, Graça Coutinho, Martin Votava and Jean-Michel Cardot
Pharmaceutics 2023, 15(7), 1863; https://doi.org/10.3390/pharmaceutics15071863 - 01 Jul 2023
Cited by 2 | Viewed by 1660
Abstract
This study aimed to link pharmacokinetic (PK) data from different flurbiprofen preparations for the treatment of sore throat with published data to elucidate whether early efficacy is due to the local action of flurbiprofen or a systemic effect after absorption of the swallowed [...] Read more.
This study aimed to link pharmacokinetic (PK) data from different flurbiprofen preparations for the treatment of sore throat with published data to elucidate whether early efficacy is due to the local action of flurbiprofen or a systemic effect after absorption of the swallowed drug. Three comparative bioavailability studies conducted in healthy subjects provided data from flurbiprofen 8.75 mg formulations, including spray solution, spray gel, lozenges, and granules. A parallel interstudy comparison was made of PK parameters, including partial AUCs (pAUCs), using an ANOVA model with the calculation of 90% confidence intervals (CI) for the differences between least squares (LS) means for each of the test groups versus the respective reference groups. All three studies showed bioequivalence for the respective product comparisons. The interstudy comparison showed a slower rate of absorption for granules compared to spray solution (reference) based on Tmax, Cmax, and pAUCs for 1 h and 2 h. When AUC0.25h and AUC0.5h were considered, slower rates of absorption were also seen for lozenges and spray gel. The differences correlated with the reported time of onset of action, which is faster for the spray solution (20 min) compared to lozenges (26 min) and granules (30 min). These pAUCs provide useful data that allow for the discrimination between formulations. Moreover, the pAUC values represent <5% of the total AUC, suggesting that the early onset of pain relief is a response to immediate local absorption at the site of action rather than a systemic effect. Full article
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32 pages, 3666 KiB  
Article
Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies
by Sara Carolina Henriques, João Albuquerque, Paulo Paixão, Luís Almeida and Nuno Elvas Silva
Pharmaceutics 2023, 15(5), 1430; https://doi.org/10.3390/pharmaceutics15051430 - 07 May 2023
Cited by 1 | Viewed by 2279
Abstract
Pilot bioavailability/bioequivalence (BA/BE) studies are usually conducted and analysed similarly to pivotal studies. Their analysis and interpretation of results usually rely on the application of the average bioequivalence approach. However, due to the small study size, pilot studies are inarguably more sensitive to [...] Read more.
Pilot bioavailability/bioequivalence (BA/BE) studies are usually conducted and analysed similarly to pivotal studies. Their analysis and interpretation of results usually rely on the application of the average bioequivalence approach. However, due to the small study size, pilot studies are inarguably more sensitive to variability. The aim of this work is to propose alternative approaches to the average bioequivalence methodology, in a way to overcome and reduce the uncertainty on the conclusions of these studies and on the potential of test formulations. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling. Each simulated BA/BE trial was analysed using the average bioequivalence approach. As alternative analyses, the centrality of the test-to-reference geometric least square means ratio (GMR), bootstrap bioequivalence analysis, and arithmetic (Amean) and geometric (Gmean) mean ƒ2 factor approaches were investigated. Methods performance was measured with a confusion matrix. The Gmean ƒ2 factor using a cut-off of 35 was the most appropriate method in the simulation conditions frame, enabling to more accurately conclude the potential of test formulations, with a reduced sample size. For simplification, a decision tree is also proposed for appropriate planning of the sample size and subsequent analysis approach to be followed in pilot BA/BE trials. Full article
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Review

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15 pages, 332 KiB  
Review
Caco-2 Cell Line Standardization with Pharmaceutical Requirements and In Vitro Model Suitability for Permeability Assays
by Marta Kus, Izabela Ibragimow and Hanna Piotrowska-Kempisty
Pharmaceutics 2023, 15(11), 2523; https://doi.org/10.3390/pharmaceutics15112523 - 24 Oct 2023
Cited by 3 | Viewed by 1796
Abstract
The Caco-2 cell line derived from human colon carcinoma is commonly used to assess the permeability of compounds in in vitro conditions. Due to the significant increase in permeability studies using the Caco-2 cell line in recent years, the need to standardize this [...] Read more.
The Caco-2 cell line derived from human colon carcinoma is commonly used to assess the permeability of compounds in in vitro conditions. Due to the significant increase in permeability studies using the Caco-2 cell line in recent years, the need to standardize this biological model seems necessary. The pharmaceutical requirements define only the acceptance criteria for the validation of the Caco-2 cell line and do not specify the protocol for its implementation. Therefore, the aim of this study is to review the conditions for permeability studies across the Caco-2 monolayer reported in the available literature concerning validation guidelines. We summarized the main aspects affecting the validation process of the Caco-2 cell line, including the culture conditions, cytotoxicity, cell differentiation process, and monolayer transport conditions, and the main conclusions may be useful in developing individual methods for preparing the cell line for validation purposes and further permeability research. Full article
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