Physiologically based in vitro – in vivo correlation of modified release oral formulations with non-linear intestinal absorption: A case study using mirabegron
{"title":"Physiologically based in vitro – in vivo correlation of modified release oral formulations with non-linear intestinal absorption: A case study using mirabegron","authors":"Yoshinori Takahashi, Atsushi Kambayashi","doi":"10.1016/j.ejpb.2024.114479","DOIUrl":null,"url":null,"abstract":"<div><p>Establishing an <em>in vitro</em> – <em>in vivo</em> correlation (IVIVC) for oral modified release (MR) formulations would make it possible to substitute an <em>in vitro</em> dissolution test for human bioequivalence (BE) studies when changing the formulation or manufacturing methods. However, the number of IVIVC applications and approvals are reportedly low. One of the main reasons for failure to obtain IVIVCs using conventional methodologies may be the lack of consideration of the dissolution and absorption mechanisms of drugs in the physiological environment. In particular, it is difficult to obtain IVIVC using conventional methodologies for drugs with non-linear absorption processes. Therefore, the aim of the present study was to develop a physiologically based biopharmaceutics model (PBBM) that enables Level A IVIVCs for mirabegron MR formulations with non-linear absorption characteristics.</p><p>Using human pharmacokinetic (PK) data for immediate-release formulations of mirabegron, the luminal drug concentration-dependent membrane permeation coefficient was calculated through curve fitting. The membrane permeation coefficient data were then applied to the human PK data of the MR formulations to estimate the <em>in vivo</em> dissolution rate by curve fitting. It was assumed that <em>in vivo</em> dissolution could be described using a zero-order rate equation. Furthermore, a Levy plot was generated using the estimated <em>in vivo</em> dissolution rate and the <em>in vitro</em> dissolution rate obtained from the literature. Finally, the dissolution rate of the MR formulations from the Levy plot was applied to the PBBM to predict the oral PK of the mirabegron MR formulations.</p><p>This PB-IVIVC approach successfully generated linear Levy plots with slopes of almost 1.0 for MR formulations with different dose strengths and dissolution rates. The Cmax values of the MR formulations were accurately predicted using this approach, whereas the prediction errors for AUC exceeded the Level A IVIVC criteria. This can be attributed to the incomplete description of colonic absorption in the current PBBM.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114479"},"PeriodicalIF":4.4000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124003059/pdfft?md5=a5f2185c9c11d839d13a2add72eed60f&pid=1-s2.0-S0939641124003059-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Pharmaceutics and Biopharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0939641124003059","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Establishing an in vitro – in vivo correlation (IVIVC) for oral modified release (MR) formulations would make it possible to substitute an in vitro dissolution test for human bioequivalence (BE) studies when changing the formulation or manufacturing methods. However, the number of IVIVC applications and approvals are reportedly low. One of the main reasons for failure to obtain IVIVCs using conventional methodologies may be the lack of consideration of the dissolution and absorption mechanisms of drugs in the physiological environment. In particular, it is difficult to obtain IVIVC using conventional methodologies for drugs with non-linear absorption processes. Therefore, the aim of the present study was to develop a physiologically based biopharmaceutics model (PBBM) that enables Level A IVIVCs for mirabegron MR formulations with non-linear absorption characteristics.
Using human pharmacokinetic (PK) data for immediate-release formulations of mirabegron, the luminal drug concentration-dependent membrane permeation coefficient was calculated through curve fitting. The membrane permeation coefficient data were then applied to the human PK data of the MR formulations to estimate the in vivo dissolution rate by curve fitting. It was assumed that in vivo dissolution could be described using a zero-order rate equation. Furthermore, a Levy plot was generated using the estimated in vivo dissolution rate and the in vitro dissolution rate obtained from the literature. Finally, the dissolution rate of the MR formulations from the Levy plot was applied to the PBBM to predict the oral PK of the mirabegron MR formulations.
This PB-IVIVC approach successfully generated linear Levy plots with slopes of almost 1.0 for MR formulations with different dose strengths and dissolution rates. The Cmax values of the MR formulations were accurately predicted using this approach, whereas the prediction errors for AUC exceeded the Level A IVIVC criteria. This can be attributed to the incomplete description of colonic absorption in the current PBBM.
期刊介绍:
The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics.
Topics covered include for example:
Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids)
Aspects of manufacturing process design
Biomedical aspects of drug product design
Strategies and formulations for controlled drug transport across biological barriers
Physicochemical aspects of drug product development
Novel excipients for drug product design
Drug delivery and controlled release systems for systemic and local applications
Nanomaterials for therapeutic and diagnostic purposes
Advanced therapy medicinal products
Medical devices supporting a distinct pharmacological effect.