Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition

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

Deadline for manuscript submissions: 10 March 2025 | Viewed by 5288

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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 Colleagues,

The incomplete systemic absorption of drugs following extravascular administration is a common occurrence, influenced by various factors such as formulation issues, the physicochemical properties of the drug, affinity to carrier-mediated transport systems, and chemical and metabolic stability. In the first volume of our Special Issue on "Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence", we concentrated on novel tools and methodologies for determining systemic bioavailability (BA), defined as the rate and extent to which a drug is absorbed from a pharmaceutical form and becomes available at the site of action, and bioequivalence (BE), defined as a sufficient similarity in bioavailability between two drug products, allowing for the assumption to be made that both products will present the same efficacy and safety (https://www.mdpi.com/journal/pharmaceutics/special_issues/GCW09W3EF7).

Understanding the extent of absorption in BA studies is crucial for determining the appropriate extravascular dosage. Similarly, achieving a similar rate and extent of absorption in BE testing facilitates the extrapolation of therapeutic outcomes between different pharmaceutical drug products. While these characteristics are traditionally evaluated through in vivo studies, the increasing complexity of new drug molecules and formulation technologies has prompted the pharmaceutical industry and regulatory agencies to seek alternative approaches. These approaches may either enhance study designs or even lead to study waivers for BA and BE assessments. This is exemplified by the recent openness to consider the necessity of conducting oral fed and proton-pump inhibitor interaction studies when developing immediate-release solid oral generic drug products by taking into consideration a comprehensive analysis of formulation differences, excipients, molecular properties, in vitro behavior, and physiological-induced changes.

In this second volume of our Special Issue on Drug Product Performance, we will continue to explore new tools and methodologies for establishing systemic bioavailability and bioequivalence. This includes in silico, in vitro, and in vivo methods. While various approaches will be accepted, we particularly encourage submissions of works utilizing integrative methodologies such a physiologically-based biopharmaceutical models (PBBM). We invite researchers, drug developers, and regulators to contribute original research or review articles offering expert opinions and perspectives in this field.

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

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Published Papers (6 papers)

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Research

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15 pages, 2373 KiB  
Article
Selection of In Vivo Relevant Dissolution Test Parameters for the Development of Cannabidiol Formulations with Enhanced Oral Bioavailability
by Nathan Koch, Quentin Bourcy, Olivier Jennotte, Patrice Chiap, Anna Lechanteur, Jean-Michel Cardot and Brigitte Evrard
Pharmaceutics 2025, 17(1), 79; https://doi.org/10.3390/pharmaceutics17010079 - 9 Jan 2025
Viewed by 665
Abstract
Background: Cannabidiol (CBD) shows interesting therapeutic properties but has yet to demonstrate its full potential in clinical trials partly due to its low solubility in physiologic media. Two different formulations of CBD (amorphous and lipid-based) have been optimized and enable an increase in [...] Read more.
Background: Cannabidiol (CBD) shows interesting therapeutic properties but has yet to demonstrate its full potential in clinical trials partly due to its low solubility in physiologic media. Two different formulations of CBD (amorphous and lipid-based) have been optimized and enable an increase in bioavailability in piglets. In vivo studies are time-consuming, costly and life-threatening. Therefore, we need to develop in vitro tests that can predict what will happen in vivo. Methods: Comparisons in terms of dissolution were made especially by using different media (FaSSGF, FaSSIF, FeSSIF, HCl 0.1N with or without SLS, phosphate buffer pH 6.8 with or without SLS) and different conditions (sink or non-sink conditions). These in vitro results were confronted with in vivo results to select the most appropriate dissolution test conditions. Results: The importance of the presence of surfactants to enable solubilization of CBD was demonstrated. Neutral media enabled a relatively good prediction of the extent of absorption observed in vivo, whereas the rate of absorption was more complicated to predict. Conclusions: FeSSIF media, and FaSSIF sink media to a lesser extent, were the only compositions enabling predictions of both extent and rate, indicating that emulsification is possibly a major contributor to the in vivo availability of the drug. Full article
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13 pages, 2081 KiB  
Article
FDA and EMA Oversight of Disruptive Science on Application of Finite Absorption Time (F.A.T.) Concept in Oral Drug Absorption: Time for Scientific and Regulatory Changes
by Elias Toulitsis, Athanasios A. Tsekouras and Panos Macheras
Pharmaceutics 2024, 16(11), 1435; https://doi.org/10.3390/pharmaceutics16111435 - 11 Nov 2024
Viewed by 890
Abstract
Background: It has been demonstrated that the concept of infinite absorption time, associated with the absorption rate constant, which drives a drug’s gastrointestinal absorption rate, is not physiologically sound. The recent analysis of oral drug absorption data based on the finite absorption time [...] Read more.
Background: It has been demonstrated that the concept of infinite absorption time, associated with the absorption rate constant, which drives a drug’s gastrointestinal absorption rate, is not physiologically sound. The recent analysis of oral drug absorption data based on the finite absorption time (F.A.T.) concept and the relevant physiologically based finite-time pharmacokinetic (PBFTPK) models developed provided a better physiologically sound description of oral drug absorption. Methods: In this study, we re-analyzed, using PBFTPK models, seven data sets of ketoprofen, amplodipine, theophylline (three formulations), and two formulations (reference, test) from a levonorgestrel bioequivalence study. Equations for one-compartment-model drugs, for the estimation of fraction of dose absorbed or the bioavailable fraction exclusively from oral data, were developed. Results: In all cases, meaningful estimates for (i) the number of absorption stages, namely, one for ketoprofen and the levonorgestrel formulations, two for amlodipine, the immediate-release theophylline formulation, and the extended-release Theotrim formulation, and three for the extended-release Theodur formulation, (ii) the duration of each absorption stage and the corresponding drug input rate, and (iii) the total duration of drug absorption, which ranged from 0.75 h (ketoprofen) to 11.6 h for Theodur were derived. Estimates for the bioavailable fraction of ketoprofen and two theophylline formulations exhibiting one-compartment-model kinetics were derived. Conclusions: This study provides insights into the detailed characteristics of oral drug absorption. The use of PBFTPK models in drug absorption analysis can be leveraged as a computational framework to discontinue the perpetuation of the mathematical fallacy of classical pharmacokinetic analysis based on the absorption rate constant as well as in the physiologically based pharmacokinetic (PBPK) studies and pharmacometrics. The present study is an additional piece of evidence for the scientific and regulatory changes required to be implemented by the regulatory agencies in the not-too-distant future. Full article
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14 pages, 1523 KiB  
Article
Role of In Vitro Tests in the Characterisation of Locally Applied, Locally Acting Drugs in the Throat: Application to Flurbiprofen
by Vit Perlik, Hafsa Ali, Jean M. Cardot and Anuradha Kulasekaran
Pharmaceutics 2024, 16(10), 1261; https://doi.org/10.3390/pharmaceutics16101261 - 27 Sep 2024
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Abstract
Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model [...] Read more.
Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model exists, a comparative clinical study can be performed in healthy subjects; where no surrogate endpoint is available, patients with the relevant indication need to be enrolled, with all the associated factors which could result in lack of sensitivity. Even though the need for alternative in vitro approaches has been acknowledged by both industry and regulatory bodies, the complexity of in vivo drug delivery processes makes the development of guidance documents particularly difficult. Our objective was to present in vitro approaches less classically used and to address in vivo relevance of the selected tests. Methods: This article analyses current regulatory approaches in Europe and the U.S., and highlights the key advantages of in vitro tests in terms of their sensitivity, reliability, reproducibility and in vivo relevance using locally applied flurbiprofen in various formulations. Results: The in vitro esophageal retention (IVOR) model demonstrates that the first 6–10 min after application of different flurbiprofen formulations is important for their comparison and also offers the best correlation with in vivo data using the partial area under the concentration-time curves (pAUCs). Rheological evaluations further demonstrated that the mucoadhesive properties of the gel spray formulation are based on interaction with mucin. Conclusions: Designing a relevant in vitro test requires adequate evaluation of the complexity of the drug substance, drug product, dosing conditions and delivery processes. Full article
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20 pages, 3055 KiB  
Article
Effects of Postprandial Factors and Second Meal Intake Time on Bioequivalence Investigation of Tadalafil-Loaded Orodispersible Films in Human Volunteers
by Su-Jun Park, Myung-Chul Gil, Bong-Sang Lee, Minji Jung and Beom-Jin Lee
Pharmaceutics 2024, 16(7), 915; https://doi.org/10.3390/pharmaceutics16070915 - 9 Jul 2024
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Abstract
Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis [...] Read more.
Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis of TDF in human volunteers should be investigated because the gastrointestinal environment varies periodically according to meal intervals, although commercial 20 mg TD-loaded tablets (TD-TAB, Cialis® tablet) may be taken with or without food. TDF was prepared by dispersing TD in an aqueous solution and polyethylene glycol 400 to ensure good dispersibility of the TD particles. In the fasting state, each T/R of Cmax and AUC between TD-TAB and TDF showed bioequivalence with 0.936–1.105 and 1.012–1.153, respectively, and dissolution rates in 1000 mL water containing 0.5% SLS were equivalent. In contrast, TDF was not bioequivalent to TD-TAB under the fed conditions by the Cmax T/R of 0.610–0.798. The increased dissolution rate of TDF via the micronization of drug particles and the reduced viscosity of the second meal content did not significantly affect the bioequivalence. Interestingly, an increase in second meal intake time from 4 h to 6 h resulted in the bioequivalence by the Cmax T/R of 0.851–0.998 of TD-TAB and TDF. The predictive diffusion direction model for physical digestion of TD-TAB and TDF in the stomach after the first and second meal intake was successfully simulated using computational fluid dynamics modeling, accounting for the delayed drug diffusion of TDF caused by prolonged digestion of stomach contents under postprandial conditions. Full article
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Review

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23 pages, 1444 KiB  
Review
Recent Advances in Studying In Vitro Drug Permeation Across Mucosal Membranes
by Juan Song, Zizhao Xu, Lingxiao Xie and Jie Shen
Pharmaceutics 2025, 17(2), 256; https://doi.org/10.3390/pharmaceutics17020256 - 14 Feb 2025
Viewed by 247
Abstract
Transmucosal drug products, such as aerosols, films, semisolids, suppositories, and tablets, have been developed for the treatment of various human diseases and conditions. Transmucosal drug absorption is highly influenced by the biological structures of the mucosa and the physiological environment specific to the [...] Read more.
Transmucosal drug products, such as aerosols, films, semisolids, suppositories, and tablets, have been developed for the treatment of various human diseases and conditions. Transmucosal drug absorption is highly influenced by the biological structures of the mucosa and the physiological environment specific to the administration route (e.g., nasal, rectal, and vaginal). Over the last few decades, in vitro permeation testing (IVPT) using animal tissues or in vitro cell cultures have been utilized as a cost-effective and efficient tool for evaluating drug release and permeation behavior, assisting in formulation development and quality control of transmucosal drug delivery systems. This review summarizes the key mucosal permeation barriers associated with representative transmucosal administration routes, as well as considerations for IVPT method development. It highlights various IVPT methods, including vertical diffusion cell, flow-through diffusion cell, Ussing chamber, and transwell systems. Additionally, future perspectives are discussed, such as the use of optical methods to study in vitro drug permeation and the development of in vitro–in vivo correlation (IVIVC) for transmucosal drug development. The potential of IVPT as part of in vitro bioequivalence assessment strategies for locally acting transmucosal drug products is also highlighted. Full article
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22 pages, 2565 KiB  
Review
Partial AUCs in Long-Acting Injectables: Rationale, Challenges, Variability, Usefulness, and Clinical Relevance
by Georgia Tsakiridou, Maria-Faidra-Galini Angelerou, Panagiotis Efentakis, Antonios Margaritis, Antigoni-Maria Papanastasiou and Lida Kalantzi
Pharmaceutics 2025, 17(1), 21; https://doi.org/10.3390/pharmaceutics17010021 - 26 Dec 2024
Viewed by 798
Abstract
Regulatory authorities typically require bioequivalence to be demonstrated by comparing pharmacokinetic parameters like area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax). Because in certain cases, AUC and Cmax alone may not be adequate to identify formulation [...] Read more.
Regulatory authorities typically require bioequivalence to be demonstrated by comparing pharmacokinetic parameters like area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax). Because in certain cases, AUC and Cmax alone may not be adequate to identify formulation differences in early and/or late segments of the dosing interval, partial AUCs (pAUCs) have been proposed as additional metrics to evaluate bioequivalence. Even though cut-off points for pAUCs are usually decided based on clinical relevance, the identification of the correct cut-off range remains elusive in many other cases and tends to contribute to increased pAUC estimate variabilities. The choice of meaningful cut-off points in pAUC estimates can be especially difficult in the case of long-acting injectable (LAI) products, where long dosing intervals and complex pharmacokinetic (PK) and pharmacodynamic (PD) profiles apply, but most importantly, because there is not always a clear PK/PD relationship established. In this communication, authors discuss the usefulness and challenges associated with the estimation of pAUCs in the development of generic LAI products through the review of six case studies under the lens of regulatory requirements from the two major authorities, namely the FDA and EMA. Full article
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