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Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition
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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: closed (30 November 2025) | Viewed by 34692

Special Issue Editor

Dr. Paulo Paixão

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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 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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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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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Related Special Issue

Published Papers (13 papers)

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Research

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14 pages, 1169 KB  
Article
Palbociclib Capsule: A Bioequivalence Study in Healthy Subjects Under Fed Conditions to Compare Two Formulations
by Marcelo Gomes Davanço, Thaís Pereira Vespasiano, Jessé Moisan, Maira Eduarda Zanin, Gilberto Carlos Ruggiero Bernasconi, Marcia Aparecida Antonio, Oscar Gonzalez, Milesa Sarmiento and Mélanie Groleau
Pharmaceutics 2026, 18(2), 175; https://doi.org/10.3390/pharmaceutics18020175 - 29 Jan 2026
Viewed by 552
Abstract
Background: Globally, breast cancer is the most frequently diagnosed neoplasm among women, with an estimated 2.3 million new cases reported in 2022. Treatment for hormone receptor-positive (HR+) advanced breast cancer includes aromatase inhibitors and CDK4/6 inhibitors such as palbociclib. Objective: This study evaluated [...] Read more.
Background: Globally, breast cancer is the most frequently diagnosed neoplasm among women, with an estimated 2.3 million new cases reported in 2022. Treatment for hormone receptor-positive (HR+) advanced breast cancer includes aromatase inhibitors and CDK4/6 inhibitors such as palbociclib. Objective: This study evaluated the bioequivalence and tolerability of two palbociclib capsule formulations to support the regulatory approval of a branded generic product in Latin America countries. Methods: Healthy participants were enrolled in an open-label, randomized, single-dose study using a two-treatment, two-sequence, two-period crossover design. Study participants received a single-dose test product, a palbociclib 125 mg capsule (Laboratório LKM S.A., Argentina), and a reference product, an Ibrance® 125 mg capsule (Pfizer Manufacturing Deutschland GmbH), under fed conditions separated by a 14-day washout period. Blood samples were obtained at scheduled intervals over a 72 h period following administration, and the palbociclib plasma concentrations were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were computed via non-compartmental analysis methods. A total of 52 healthy subjects were enrolled, and 50 subjects completed the study. Results: The geometric mean ratios (90% confidence intervals) for Cmax and AUC0–72 were 107.07% (101.98–112.42) and 109.77% (106.51–113.13), respectively. Conclusions: Both formulations were well-tolerated in healthy subjects. In accordance with regulatory standards, bioequivalence between the test formulation and the reference product was successfully demonstrated. Full article
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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7 pages, 763 KB  
Article
Oral Bioavailability of Monoclonal Antibody
by Ashwni Verma, Shengjia Wu and Dhaval K. Shah
Pharmaceutics 2026, 18(1), 22; https://doi.org/10.3390/pharmaceutics18010022 - 23 Dec 2025
Viewed by 1556
Abstract
Background/Objectives: Despite significant interest in the oral delivery of antibodies, the oral bioavailability of monoclonal antibodies (mAbs) is not known to date. To find out an answer to this question, we have performed a preclinical investigation in mice and rats, using a non-binding [...] Read more.
Background/Objectives: Despite significant interest in the oral delivery of antibodies, the oral bioavailability of monoclonal antibodies (mAbs) is not known to date. To find out an answer to this question, we have performed a preclinical investigation in mice and rats, using a non-binding humanized mAb trastuzumab as the prototype molecule. Methods: The antibody was administered at the dose of 100 mg/kg in mice and rats, and plasma pharmacokinetics (PK) was measured for 14 days. Published plasma PK of trastuzumab in mice and rats obtained after intravenous administration was also used for the analysis. Non-compartmental analysis (NCA), as well as compartmental modeling of PK data, was performed to estimate the oral bioavailability of the antibody in mice and rats. Results: It was found that the oral bioavailability of mAb in rats and mice determined using NCA was 0.027% and 0.014%, respectively. The model-estimated oral bioavailability of the mAb in rats and mice was 0.025% and 0.013%, respectively. The rate of absorption of the mAb from the gastrointestinal tract was found to be the same between rats and mice, as 0.78 h−1. Conclusions: Overall, the oral bioavailability of the humanized mAb in rodents was found to be around 0.02%, suggesting only 1 out of 5000 mAb molecules administered orally makes it to the systemic circulation. To the best of our knowledge, this is the first study to report an absolute oral bioavailability value for a mAb. It remains to be seen if the observed value of 0.02% is generalizable across mAb molecules and other animal species, including humans. Full article
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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19 pages, 652 KB  
Article
Exploring Experimental and Statistical Approaches to Control Oversensitivity of In Vitro Permeability to Excipient Effects
by Mauricio A. García, Alexis Aceituno, Nicole B. Díaz, Eduardo M. Tapia, Danae Contreras, Constanza López-Lagos, Virginia Sánchez and Pablo M. González
Pharmaceutics 2025, 17(9), 1110; https://doi.org/10.3390/pharmaceutics17091110 - 26 Aug 2025
Viewed by 1095
Abstract
Background/Objectives: The static in vitro permeability assay based on cell monolayers has been widely used in the pharmaceutical industry and recognized by regulatory agencies as a surrogate method for BCS classification. However, the application of such an experiment to study the effects of [...] Read more.
Background/Objectives: The static in vitro permeability assay based on cell monolayers has been widely used in the pharmaceutical industry and recognized by regulatory agencies as a surrogate method for BCS classification. However, the application of such an experiment to study the effects of formulations is limited by the oversensitivity to the excipient effect on drug permeability. In this article, we studied the effects of common excipients on the permeability of moderately and poorly absorbed model compounds across cell monolayers, using two approaches to control said oversensitivity. Methods: Drug permeability across MDCK-wt was assessed in the absence (control) or presence (treatment) of excipients, using minoxidil as a high-permeability marker. The effects of excipients were parameterized as a permeability ratio (PR = treatment/control) without or with normalization (nPR) by minoxidil permeability. Metrics were compared by either ANOVA (p < 0.01) or confidence intervals (CI90, as per bioequivalence metrics) to identify excipient effects. Results: Acyclovir and hydrochlorothiazide showed the highest and lowest number of interactions, respectively. The most impactful excipients were sodium lauryl sulfate, microcrystalline cellulose, and sodium starch glycolate. Unexpectedly, nPR increased the number of excipient effects across model drugs (19 vs. 21). Alternatively, the CI90 approach was more sensitive than ANOVA in identifying excipient effects (41 vs. 32). Conclusions: Minoxidil was not able to control the anticipated oversensitivity of cell-based permeability experiments. Meanwhile, ANOVA was overall able to reduce oversensitivity to excipient effects on drug permeability compared to CI90. Nonetheless, there might be a niche for CI90 analysis when comparing the performance of two formulations on the permeability of moderately and poorly absorbed drugs. Full article
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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27 pages, 9025 KB  
Article
Optimization, In Vitro, and In Silico Characterization of Theophylline Inhalable Powder Using Raffinose-Amino Acid Combination as Fine Co-Spray-Dried Carriers
by Petra Party, Lomass Soliman, Attila Nagy, Árpád Farkas and Rita Ambrus
Pharmaceutics 2025, 17(4), 466; https://doi.org/10.3390/pharmaceutics17040466 - 3 Apr 2025
Cited by 4 | Viewed by 2440
Abstract
Background/Objectives: Dry powder inhalation is an attractive research area for development. Therefore, this work aimed to develop inhalable co-spray-dried theophylline (TN) microparticles, utilizing raffinose-amino acid fine carriers intended for asthma therapy. The study addressed enhancing TN’s physicochemical and aerodynamic properties to ensure [...] Read more.
Background/Objectives: Dry powder inhalation is an attractive research area for development. Therefore, this work aimed to develop inhalable co-spray-dried theophylline (TN) microparticles, utilizing raffinose-amino acid fine carriers intended for asthma therapy. The study addressed enhancing TN’s physicochemical and aerodynamic properties to ensure efficient lung deposition. Methods: The process involves spray-drying each formulation’s solution using a mini spray drier. A rigorous assessment was conducted on particle size distribution, structural and thermal analysis, morphology study, in vitro and in silico aerodynamic investigation, and aerodynamic particle counter in addition to the solubility, in vitro dissolution, and diffusion of TN. Results: The carriers containing leucine and glycine revealed superior characteristics (mass median aerodynamic diameter (MMAD): 4.6–5 µm, fine particle fraction (FPF): 30.6–35.1%, and amorphous spherical structure) as candidates for further development of TN-DPIs, while arginine was excluded due to intensive aggregation and hygroscopicity, which led to poor aerodynamic performance. TN co-spray-dried samples demonstrated fine micronized particles (D [0.5]: 3.99–5.96 µm) with predominantly amorphous structure (crystallinity index: 24.1–45.2%) and significant solubility enhancement (~19-fold). Formulations containing leucine and leucine-glycine revealed the highest FPF (45.7–47.8%) and in silico lung deposition (39.3–40.1%), rapid in vitro drug release (~100% within 10 min), and improved in vitro diffusion (2.29–2.43-fold), respectively. Moreover, the aerodynamic counter confirmed the development of fine microparticles (mean number particle size = 2.3–2.02 µm). Conclusions: This innovative formulation possesses enhanced physicochemical, morphological, and aerodynamic characteristics of low-dose TN for local asthma treatment and could be applied as a promising carrier for dry powder inhaler development. Full article
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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16 pages, 2318 KB  
Article
Physiologically Based Biopharmaceutics Model of Apixaban for Biopharmaceutics Risk Assessment
by Paulo Paixão, Zvonimir Petric and José A. G. Morais
Pharmaceutics 2025, 17(3), 382; https://doi.org/10.3390/pharmaceutics17030382 - 18 Mar 2025
Cited by 1 | Viewed by 1836
Abstract
Background/Objectives: This study applies a Physiologically Based Biopharmaceutics Modeling (PBBM) framework to predict the bioavailability (BA) and bioequivalence (BE) of apixaban, a borderline BCS Class III/IV drug. It investigates how formulation factors, such as particle size, granulation method, and dissolution conditions, affect apixaban’s [...] Read more.
Background/Objectives: This study applies a Physiologically Based Biopharmaceutics Modeling (PBBM) framework to predict the bioavailability (BA) and bioequivalence (BE) of apixaban, a borderline BCS Class III/IV drug. It investigates how formulation factors, such as particle size, granulation method, and dissolution conditions, affect apixaban’s in vivo behavior under fasting conditions. Methods: A PBBM approach was developed by integrating physicochemical, formulation, and drug-related parameters to simulate dissolution and absorption using a middle-out strategy for combining in silico, in vitro, and in vivo data. The Noyes–Whitney equation was used to predict dissolution influenced by particle size, granulation type, and in vitro dissolution conditions. This information was added to a compartmental absorption model of the gastrointestinal track connected to a classical compartmental model characterizing apixaban’s disposition. Results: The study validated the apixaban PBBM predictions by comparing simulated and observed pharmacokinetic profiles across several doses and immediate release formulations (solution and tablets) administered through the oral route. Results demonstrated acceptable prediction accuracy for BA and BE under various conditions. The model’s simulations identified a dissolution safe space, enabling regulatory and development insights into acceptable formulation characteristics. Conclusions: These findings highlight the potential of PBBM in streamlining drug development, reducing clinical studies, and supporting regulatory decisions. Specifically, for apixaban, the study demonstrated that particle sizes below 120 µm ensure BE with reference formulations, while formulations with faster dissolution rates, such as smaller particle sizes, align closely with BCS biowaiver criteria. This research emphasizes PBBM as a valuable tool for optimizing drug quality and lifecycle management. Full article
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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15 pages, 2373 KB  
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
Cited by 1 | Viewed by 2067
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
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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13 pages, 2081 KB  
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
Cited by 2 | Viewed by 1958
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
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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14 pages, 1523 KB  
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
Viewed by 2084
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
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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20 pages, 3055 KB  
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
Cited by 1 | Viewed by 5743
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
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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Review

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42 pages, 2703 KB  
Review
Surfactant–Particle Engineering Hybrids: Emerging Strategies for Enhancing Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs
by Kyeong-Soo Kim, Hyuk Jun Cho, Fakhar Ud Din, Jung Hyun Cho and Han-Gon Choi
Pharmaceutics 2026, 18(1), 37; https://doi.org/10.3390/pharmaceutics18010037 - 26 Dec 2025
Cited by 1 | Viewed by 1212
Abstract
Background/Objectives: The poor aqueous solubility of many therapeutic compounds remains a key barrier to achieving optimal oral bioavailability. While traditional formulation strategies—such as surfactant-based solubilization, nanocrystals, and amorphous solid dispersions—have yielded varying degrees of success, they are often limited by poor physical stability, [...] Read more.
Background/Objectives: The poor aqueous solubility of many therapeutic compounds remains a key barrier to achieving optimal oral bioavailability. While traditional formulation strategies—such as surfactant-based solubilization, nanocrystals, and amorphous solid dispersions—have yielded varying degrees of success, they are often limited by poor physical stability, high excipient loads, inconsistent absorption, and safety concerns associated with long-term surfactant exposure. To address these challenges, this review evaluates surfactant–particle hybrid drug delivery systems as a next-generation platform for enhancing the oral delivery of poorly water-soluble drugs. Methods: A comprehensive literature analysis was conducted to examine the mechanistic foundations, formulation techniques, and translational hurdles associated with these hybrid systems. Representative in vitro and in vivo case studies were critically reviewed to assess performance consistency, particularly with respect to dissolution enhancement, supersaturation stabilization, and permeability modulation. Consideration was also given to manufacturing feasibility, excipient safety, scalability, and regulatory constraints. Results: Findings indicate that surfactant–particle hybrids provide synergistic benefits by integrating solubilization and stabilization functions with tailored particle design. These systems have shown consistent improvements in pharmacokinetic profiles and drug absorption across diverse drug candidates. However, limitations remain, including challenges in long-term physical stability and excipient compatibility that must be addressed for broader application. Conclusions: Surfactant–particle hybrid systems offer a versatile and promising approach to overcoming the limitations of poorly soluble drugs. With careful attention to formulation optimization and regulatory compliance, they have the potential to serve as a transformative platform in future oral drug delivery strategies. Full article
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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17 pages, 1424 KB  
Review
Challenges in the Investigation of Therapeutic Equivalence of Locally Applied/Locally Acting Drugs in the Gastrointestinal Tract: The Rifaximin Case
by Georgia Tsakiridou, Antigoni Maria Papanastasiou, Panagiotis Efentakis, Maria Faidra Galini Angelerou and Lida Kalantzi
Pharmaceutics 2025, 17(7), 839; https://doi.org/10.3390/pharmaceutics17070839 - 27 Jun 2025
Viewed by 3145
Abstract
Background: Locally acting gastrointestinal (GI) drugs present challenges for generic drug development because traditional bioequivalence measures, which rely on systemic drug levels, do not reflect local efficacy. This review examines regulatory guidelines for establishing therapeutic equivalence for such drugs, using rifaximin—a minimally absorbed, [...] Read more.
Background: Locally acting gastrointestinal (GI) drugs present challenges for generic drug development because traditional bioequivalence measures, which rely on systemic drug levels, do not reflect local efficacy. This review examines regulatory guidelines for establishing therapeutic equivalence for such drugs, using rifaximin—a minimally absorbed, gut-localized antibiotic—as a case study. Methods: We reviewed bioequivalence guidelines from the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA), along with the literature on rifaximin’s biopharmaceutical and clinical properties, to identify strategies and challenges for establishing equivalence for locally acting GI drugs. Results: Rifaximin exemplifies the limitations of standard bioequivalence methods: as a Biopharmaceutics Classification System (BCS) class IV drug with minimal absorption and low solubility, in vitro dissolution may not predict local drug availability. Clinical endpoint trials (e.g., traveler’s diarrhea, hepatic encephalopathy, IBS-D) are resource-intensive and insensitive to formulation differences. Pharmacokinetic (PK) studies in healthy volunteers show low, variable plasma levels, which may inaccurately discriminate between formulations. The EMA requires evidence of non-saturable absorption to accept PK data, a difficult-to-establish but potentially irrelevant criterion. Differences between FDA and EMA approaches highlight a lack of harmonization, complicating global generic development. Conclusions: A tailored, multifaceted approach is needed to demonstrate bioequivalence for GI-localized drugs like rifaximin. This case underscores the need for more sensitive surrogate methods (e.g. advanced in vitro or pharmacodynamic models) and flexible regulatory criteria. Harmonization across international guidelines and innovative bioequivalence study designs are key to facilitating the approval of safe and effective generic alternatives in this drug class. Full article
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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21 pages, 1444 KB  
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
Cited by 8 | Viewed by 4766
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
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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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 4452
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
(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)
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