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Special Issue "Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence"

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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 4392

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Dr. Paulo Paixão

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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

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 (5 papers)

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Research

Open AccessArticle

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

and

Pharmaceutics 2023, 15(9), 2366; https://doi.org/10.3390/pharmaceutics15092366 - 21 Sep 2023

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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 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 (AUC_0-t, AUC_0-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

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence)

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Open AccessArticle

Understanding Discordance between In Vitro Dissolution, Local Gut and Systemic Bioequivalence of Budesonide in Healthy and Crohn’s Disease Patients through PBPK Modeling

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 649

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 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

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence)

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Open AccessArticle

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

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

Viewed by 347

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 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 C_max, AUC₀^∞, AUC₀^Cmax, and T_max (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 f_2, 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

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence)

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Open AccessArticle

Relationship between Pharmacokinetic Profile and Clinical Efficacy Data of Three Different Forms of Locally Applied Flurbiprofen in the Mouth/Throat

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Pharmaceutics 2023, 15(7), 1863; https://doi.org/10.3390/pharmaceutics15071863 - 01 Jul 2023

Viewed by 977

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 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 T_max, C_max, and pAUCs for 1 h and 2 h. When AUC_0.25h and AUC_0.5h 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

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence)

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Open AccessArticle

Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies

Sara Carolina Henriques

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Pharmaceutics 2023, 15(5), 1430; https://doi.org/10.3390/pharmaceutics15051430 - 07 May 2023

Viewed by 1463

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 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 (A_mean) and geometric (G_mean) mean ƒ₂ factor approaches were investigated. Methods performance was measured with a confusion matrix. The G_mean 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

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence)

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