Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling

While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dep...

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Published in:	The AAPS journal Vol. 24; no. 1; p. 21
Main Authors:	Bego, Margareta, Patel, Nikunjkumar, Cristofoletti, Rodrigo, Rostami-Hodjegan, Amin
Format:	Journal Article
Language:	English
Published:	Cham Springer International Publishing 05.01.2022 Springer
Subjects:	Adolescent Adult Biochemistry Biological Availability Biomedical and Life Sciences Biomedicine Biotechnology Cross-Over Studies Delayed-Action Preparations Gastrointestinal Tract - physiology Humans Male Medical research Medicine, Experimental Middle Aged Models, Biological Pharmacology/Toxicology Pharmacy Physiological aspects Posaconazole Proof of Concept Study Research Article Research Design Theme: Integrating In Vitro Systems and Physiologically-Based Pharmacokinetics Modeling to Optimize Drug Product Development Therapeutic Equivalency Triazoles - administration & dosage Triazoles - pharmacokinetics Young Adult intra-subject variation virtual bioequivalence physiology-based pharmacokinetics within-subject variability
ISSN:	1550-7416, 1550-7416
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Abstract	While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as ‘not plausible’. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract
AbstractList	While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as ‘not plausible’. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as 'not plausible'. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract.While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as 'not plausible'. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract. While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as ‘not plausible’. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as 'not plausible'. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract. While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as 'not plausible'. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as ‘not plausible’. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations.
ArticleNumber	21
Audience	Academic
Author	Rostami-Hodjegan, Amin Cristofoletti, Rodrigo Bego, Margareta Patel, Nikunjkumar
Author_xml	– sequence: 1 givenname: Margareta orcidid: 0000-0003-0278-9730 surname: Bego fullname: Bego, Margareta email: margareta.bego@halmed.hr organization: Agency for Medicinal Products and Medical Devices (HALMED), Centre for Applied Pharmacokinetic Research (CAPKR), School of Health Sciences, University of Manchester – sequence: 2 givenname: Nikunjkumar surname: Patel fullname: Patel, Nikunjkumar organization: Certara UK Limited, Simcyp Division – sequence: 3 givenname: Rodrigo surname: Cristofoletti fullname: Cristofoletti, Rodrigo organization: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida – sequence: 4 givenname: Amin surname: Rostami-Hodjegan fullname: Rostami-Hodjegan, Amin organization: Centre for Applied Pharmacokinetic Research (CAPKR), School of Health Sciences, University of Manchester, Certara UK Limited, Simcyp Division
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Cites_doi	10.1016/j.xphs.2016.10.008 10.1016/j.ejpb.2018.03.002 10.1208/s12248-009-9099-y 10.1016/j.xphs.2015.11.033 10.1208/s12248-008-9015-x 10.1038/ctg.2015.22 10.1021/acs.molpharmaceut.6b00497 10.1016/j.ejps.2019.105170 10.1016/j.ejps.2017.07.035 10.1007/s11095-008-9580-9 10.1016/j.xphs.2017.08.002 10.1016/j.xphs.2018.06.013 10.1021/acs.molpharmaceut.0c00903 10.1002/bdd.2257 10.1002/cpt.1242 10.1002/jps.2600821125 10.1208/s12248-020-00495-4 10.1016/j.ejps.2016.10.036 10.1111/bcp.13826 10.1128/AAC.04223-14 10.3109/03602538409015066 10.1002/jps.24474 10.1021/acs.molpharmaceut.7b00396 10.5414/CPP43485 10.1208/s12249-014-0194-8 10.1208/s12248-021-00564-2 10.2133/dmpk.24.53 10.1016/j.ijpharm.2018.08.042 10.1007/BF01062331 10.1208/s12248-020-00480-x 10.1111/bcp.14986
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Keywords	intra-subject variation virtual bioequivalence physiology-based pharmacokinetics within-subject variability
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References	Babiskin, Zhang (CR24) 2015; 104 Grimm, Koziolek, Kuhn, Weitschies (CR19) 2018; 127 CR15 Cristofoletti, Patel, Dressman (CR6) 2017; 106 Upton, Thiercelin, Moore, Riegelman (CR33) 1982; 10 Hens, Pathak, Mitra, Patel, Liu, Patel, Jamei, Brouwers, Augustijns, Turner (CR29) 2017; 14 El-Khateeb, Burkhill, Murby, Amirat, Rostami-Hodjegan, Ahmad (CR1) 2021; 42 Jamei, Turner, Yang, Neuhoff, Polak, Rostami-Hodjegan, Tucker (CR31) 2009; 11 Blume, Midha (CR16) 1993; 82 Davit, Conner, Fabian-Fritsch, Haidar, Jiang, Patel, Seo, Suh, Thompson, Yu (CR18) 2008; 10 Wu, Shah, Li, Duan, Zhao, Suarez (CR23) 2021; 23 Mikolajczyk, Watson, Surma, Rubin (CR21) 2015; 6 Margolskee, Darwich, Pepin, Aarons, Galetin, Rostami-Hodjegan, Carlert, Hammarberg, Hilgendorf, Johansson, Karlsson, Murphy, Tannergren, Thörn, Yasin, Mazuir, Nicolas, Ramusovic, Xu, Pathak, Korjamo, Laru, Malkki, Pappinen, Tuunainen, Dressman, Hansmann, Kostewicz, He, Heimbach, Wu, Hoft, Laplanche, Pang, Bolger, Huehn, Lukacova, Mullin, Szeto, Costales, Lin, McAllister, Modi, Rotter, Varma, Wong, Mitra, Bevernage, Biewenga, van Peer, Lloyd, Shardlow, Langguth, Mishenzon, Nguyen, Brown, Lennernäs, Abrahamsson (CR13) 2017; 96 Liu, Li, Rostami-Hodjegan, Bois, Jamei (CR32) 2020; 22 Vo, Feng, Zhang, Zhang, Repka (CR26) 2018; 550 CR8 Midha, Rawson, Hubbard (CR17) 2005; 43 Mitra, Kesisoglou, Dogterom (CR11) 2015; 16 Cristofoletti, Patel, Dressman (CR5) 2016; 105 CR28 Cristofoletti, Rowland, Lesko, Blume, Rostami-Hodjegan, Dressman (CR2) 2018; 107 Loisios-Konstantinidis, Cristofoletti, Fotaki, Turner, Dressman (CR3) 2020; 143 CR9 Mitra (CR12) 2019; 105 Pepin, Flanagan, Holt, Eidelman, Treacy, Rowlings (CR10) 2016; 13 Steimer, Mallet, Golmard, Boisvieux (CR34) 1984; 15 Berben, Brouwers, Augustijns (CR27) 2018; 107 Kersemaekers, van Iersel, Nassander, O'Mara, Waskin, Caceres, van Iersel (CR30) 2015; 59 Loisios-Konstantinidis, Dressman (CR22) 2021; 18 Yang, Ma, Bullman, Nicholls, Chen (CR14) 2019; 85 Jamei, Dickinson, Rostami-Hodjegan (CR25) 2009; 24 Doki, Darwich, Patel, Rostami-Hodjegan (CR7) 2017; 109 Ibekwe, Fadda, McConnell, Khela, Evans, Basit (CR20) 2008; 25 Loisios-Konstantinidis, Hens, Mitra, Kim, Chiann, Cristofoletti (CR4) 2020; 22 672_CR28 KK Midha (672_CR17) 2005; 43 M Jamei (672_CR31) 2009; 11 R Cristofoletti (672_CR5) 2016; 105 F Wu (672_CR23) 2021; 23 P Berben (672_CR27) 2018; 107 I Loisios-Konstantinidis (672_CR4) 2020; 22 R Cristofoletti (672_CR2) 2018; 107 XJ Pepin (672_CR10) 2016; 13 M Grimm (672_CR19) 2018; 127 AQ Vo (672_CR26) 2018; 550 A Margolskee (672_CR13) 2017; 96 BM Davit (672_CR18) 2008; 10 RA Upton (672_CR33) 1982; 10 HH Blume (672_CR16) 1993; 82 D Liu (672_CR32) 2020; 22 K Doki (672_CR7) 2017; 109 AE Mikolajczyk (672_CR21) 2015; 6 A Mitra (672_CR11) 2015; 16 672_CR15 VC Ibekwe (672_CR20) 2008; 25 WM Kersemaekers (672_CR30) 2015; 59 672_CR9 E El-Khateeb (672_CR1) 2021; 42 672_CR8 I Loisios-Konstantinidis (672_CR22) 2021; 18 B Hens (672_CR29) 2017; 14 JL Steimer (672_CR34) 1984; 15 I Loisios-Konstantinidis (672_CR3) 2020; 143 AH Babiskin (672_CR24) 2015; 104 J Yang (672_CR14) 2019; 85 M Jamei (672_CR25) 2009; 24 R Cristofoletti (672_CR6) 2017; 106 A Mitra (672_CR12) 2019; 105
References_xml	– volume: 106 start-page: 560 issue: 2 year: 2017 end-page: 569 ident: CR6 article-title: Assessment of bioequivalence of weak base formulations under various dosing conditions using physiologically based pharmacokinetic simulations in virtual populations. Case Examples: Ketoconazole and Posaconazole publication-title: J Pharm Sci. doi: 10.1016/j.xphs.2016.10.008 – volume: 127 start-page: 309 year: 2018 end-page: 317 ident: CR19 article-title: Interindividual and intraindividual variability of fasted state gastric fluid volume and gastric emptying of water publication-title: Eur J Pharm Biopharm. doi: 10.1016/j.ejpb.2018.03.002 – volume: 11 start-page: 225 issue: 2 year: 2009 end-page: 237 ident: CR31 article-title: Population-based mechanistic prediction of oral drug absorption publication-title: AAPS J. doi: 10.1208/s12248-009-9099-y – volume: 105 start-page: 2712 issue: 9 year: 2016 end-page: 2722 ident: CR5 article-title: Differences in food effects for 2 weak bases with similar BCS drug-related properties: what is happening in the intestinal lumen? publication-title: J Pharm Sci. doi: 10.1016/j.xphs.2015.11.033 – volume: 10 start-page: 148 issue: 1 year: 2008 end-page: 156 ident: CR18 article-title: Highly variable drugs: observations from bioequivalence data submitted to the FDA for new generic drug applications publication-title: AAPS J. doi: 10.1208/s12248-008-9015-x – volume: 6 year: 2015 ident: CR21 article-title: Assessment of tandem measurements of pH and total gut transit time in healthy volunteers publication-title: Clin Transl Gastroenterol. doi: 10.1038/ctg.2015.22 – volume: 13 start-page: 3256 issue: 9 year: 2016 end-page: 3269 ident: CR10 article-title: Justification of drug product dissolution rate and drug substance particle size specifications based on absorption PBPK modeling for lesinurad immediate release tablets publication-title: Mol Pharm. doi: 10.1021/acs.molpharmaceut.6b00497 – volume: 143 start-page: 105170 year: 2020 ident: CR3 article-title: Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically based population pharmacokinetic modeling. Case example: Naproxen publication-title: Eur J Pharm Sci. doi: 10.1016/j.ejps.2019.105170 – volume: 109 start-page: 111 year: 2017 end-page: 120 ident: CR7 article-title: Virtual bioequivalence for achlorhydric subjects: the use of PBPK modelling to assess the formulation-dependent effect of achlorhydria publication-title: Eur J Pharm Sci. doi: 10.1016/j.ejps.2017.07.035 – volume: 25 start-page: 1828 issue: 8 year: 2008 end-page: 1835 ident: CR20 article-title: Interplay between intestinal pH, transit time and feed status on the in vivo performance of pH responsive ileo-colonic release systems publication-title: Pharm Res. doi: 10.1007/s11095-008-9580-9 – volume: 107 start-page: 250 issue: 1 year: 2018 end-page: 256 ident: CR27 article-title: Assessment of passive intestinal permeability using an artificial membrane insert system publication-title: J Pharm Sci. doi: 10.1016/j.xphs.2017.08.002 – ident: CR8 – volume: 107 start-page: 2519 issue: 10 year: 2018 end-page: 2530 ident: CR2 article-title: Past, present, and future of bioequivalence: improving assessment and extrapolation of therapeutic equivalence for oral drug products publication-title: J Pharm Sci. doi: 10.1016/j.xphs.2018.06.013 – volume: 18 start-page: 1 issue: 1 year: 2021 end-page: 17 ident: CR22 article-title: Physiologically based pharmacokinetic/pharmacodynamic modeling to support waivers of in vivo clinical studies: current status, challenges, and opportunities publication-title: Mol Pharm. doi: 10.1021/acs.molpharmaceut.0c00903 – volume: 42 start-page: 107 issue: 4 year: 2021 end-page: 117 ident: CR1 article-title: Physiological-based pharmacokinetic modeling trends in pharmaceutical drug development over the last 20-years; in-depth analysis of applications, organizations, and platforms publication-title: Biopharm Drug Dispos. doi: 10.1002/bdd.2257 – volume: 105 start-page: 307 issue: 2 year: 2019 end-page: 309 ident: CR12 article-title: Maximizing the role of physiologically based oral absorption modeling in generic drug development publication-title: Clin Pharmacol Ther. doi: 10.1002/cpt.1242 – volume: 82 start-page: 1186 issue: 11 year: 1993 end-page: 1189 ident: CR16 article-title: Bio-International 92, conference on bioavailability, bioequivalence, and pharmacokinetic studies publication-title: J Pharm Sci. doi: 10.1002/jps.2600821125 – volume: 22 start-page: 113 issue: 5 year: 2020 ident: CR4 article-title: Using physiologically based pharmacokinetic modeling to assess the risks of failing bioequivalence criteria: a tale of two ibuprofen products publication-title: AAPS J. doi: 10.1208/s12248-020-00495-4 – volume: 96 start-page: 610 year: 2017 end-page: 625 ident: CR13 article-title: IMI - Oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 2: an introduction to the simulation exercise and overview of results publication-title: Eur J Pharm Sci. doi: 10.1016/j.ejps.2016.10.036 – volume: 85 start-page: 563 issue: 3 year: 2019 end-page: 569 ident: CR14 article-title: Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel-group study of lamotrigine publication-title: Br J Clin Pharmacol. doi: 10.1111/bcp.13826 – volume: 59 start-page: 1246 issue: 2 year: 2015 end-page: 1251 ident: CR30 article-title: Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects publication-title: Antimicrob Agents Chemother. doi: 10.1128/AAC.04223-14 – ident: CR15 – volume: 15 start-page: 265 issue: 1-2 year: 1984 end-page: 292 ident: CR34 article-title: Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model publication-title: Drug Metab Rev. doi: 10.3109/03602538409015066 – volume: 104 start-page: 3170 issue: 9 year: 2015 end-page: 3182 ident: CR24 article-title: Application of physiologically based absorption modeling for amphetamine salts drug products in generic drug evaluation publication-title: J Pharm Sci. doi: 10.1002/jps.24474 – ident: CR9 – volume: 14 start-page: 4321 issue: 12 year: 2017 end-page: 4333 ident: CR29 article-title: In silico modeling approach for the evaluation of gastrointestinal dissolution, supersaturation, and precipitation of posaconazole publication-title: Mol Pharm. doi: 10.1021/acs.molpharmaceut.7b00396 – volume: 43 start-page: 485 issue: 10 year: 2005 end-page: 498 ident: CR17 article-title: The bioequivalence of highly variable drugs and drug products publication-title: Int J Clin Pharmacol Ther. doi: 10.5414/CPP43485 – volume: 16 start-page: 76 issue: 1 year: 2015 end-page: 84 ident: CR11 article-title: Application of absorption modeling to predict bioequivalence outcome of two batches of etoricoxib tablets publication-title: AAPS PharmSciTech. doi: 10.1208/s12249-014-0194-8 – volume: 23 start-page: 31 issue: 2 year: 2021 ident: CR23 article-title: Biopharmaceutics applications of physiologically based pharmacokinetic absorption modeling and simulation in regulatory submissions to the U.S. Food and Drug Administration for New Drugs publication-title: AAPS J. doi: 10.1208/s12248-021-00564-2 – volume: 24 start-page: 53 issue: 1 year: 2009 end-page: 75 ident: CR25 article-title: A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates publication-title: Drug Metab Pharmacokinet. doi: 10.2133/dmpk.24.53 – volume: 550 start-page: 216 issue: 1-2 year: 2018 end-page: 228 ident: CR26 article-title: Dual mechanism of microenvironmental pH modulation and foam melt extrusion to enhance performance of HPMCAS based amorphous solid dispersion publication-title: Int J Pharm. doi: 10.1016/j.ijpharm.2018.08.042 – ident: CR28 – volume: 10 start-page: 135 issue: 2 year: 1982 end-page: 146 ident: CR33 article-title: A method for estimating within-individual variability in clearance and in volume of distribution from standard bioavailability studies publication-title: J Pharmacokinet Biopharm. doi: 10.1007/BF01062331 – volume: 22 start-page: 93 issue: 5 year: 2020 ident: CR32 article-title: Considerations and caveats when applying global sensitivity analysis methods to physiologically based pharmacokinetic models publication-title: AAPS J. doi: 10.1208/s12248-020-00480-x – volume: 24 start-page: 53 issue: 1 year: 2009 ident: 672_CR25 publication-title: Drug Metab Pharmacokinet. doi: 10.2133/dmpk.24.53 – volume: 25 start-page: 1828 issue: 8 year: 2008 ident: 672_CR20 publication-title: Pharm Res. doi: 10.1007/s11095-008-9580-9 – volume: 18 start-page: 1 issue: 1 year: 2021 ident: 672_CR22 publication-title: Mol Pharm. doi: 10.1021/acs.molpharmaceut.0c00903 – volume: 11 start-page: 225 issue: 2 year: 2009 ident: 672_CR31 publication-title: AAPS J. doi: 10.1208/s12248-009-9099-y – volume: 96 start-page: 610 year: 2017 ident: 672_CR13 publication-title: Eur J Pharm Sci. doi: 10.1016/j.ejps.2016.10.036 – volume: 143 start-page: 105170 year: 2020 ident: 672_CR3 publication-title: Eur J Pharm Sci. doi: 10.1016/j.ejps.2019.105170 – volume: 105 start-page: 2712 issue: 9 year: 2016 ident: 672_CR5 publication-title: J Pharm Sci. doi: 10.1016/j.xphs.2015.11.033 – volume: 106 start-page: 560 issue: 2 year: 2017 ident: 672_CR6 publication-title: J Pharm Sci. doi: 10.1016/j.xphs.2016.10.008 – ident: 672_CR9 – volume: 10 start-page: 135 issue: 2 year: 1982 ident: 672_CR33 publication-title: J Pharmacokinet Biopharm. doi: 10.1007/BF01062331 – volume: 107 start-page: 2519 issue: 10 year: 2018 ident: 672_CR2 publication-title: J Pharm Sci. doi: 10.1016/j.xphs.2018.06.013 – volume: 104 start-page: 3170 issue: 9 year: 2015 ident: 672_CR24 publication-title: J Pharm Sci. doi: 10.1002/jps.24474 – volume: 42 start-page: 107 issue: 4 year: 2021 ident: 672_CR1 publication-title: Biopharm Drug Dispos. doi: 10.1002/bdd.2257 – volume: 13 start-page: 3256 issue: 9 year: 2016 ident: 672_CR10 publication-title: Mol Pharm. doi: 10.1021/acs.molpharmaceut.6b00497 – volume: 16 start-page: 76 issue: 1 year: 2015 ident: 672_CR11 publication-title: AAPS PharmSciTech. doi: 10.1208/s12249-014-0194-8 – volume: 85 start-page: 563 issue: 3 year: 2019 ident: 672_CR14 publication-title: Br J Clin Pharmacol. doi: 10.1111/bcp.13826 – volume: 127 start-page: 309 year: 2018 ident: 672_CR19 publication-title: Eur J Pharm Biopharm. doi: 10.1016/j.ejpb.2018.03.002 – ident: 672_CR15 doi: 10.1111/bcp.14986 – volume: 14 start-page: 4321 issue: 12 year: 2017 ident: 672_CR29 publication-title: Mol Pharm. doi: 10.1021/acs.molpharmaceut.7b00396 – volume: 105 start-page: 307 issue: 2 year: 2019 ident: 672_CR12 publication-title: Clin Pharmacol Ther. doi: 10.1002/cpt.1242 – volume: 82 start-page: 1186 issue: 11 year: 1993 ident: 672_CR16 publication-title: J Pharm Sci. doi: 10.1002/jps.2600821125 – volume: 550 start-page: 216 issue: 1-2 year: 2018 ident: 672_CR26 publication-title: Int J Pharm. doi: 10.1016/j.ijpharm.2018.08.042 – volume: 109 start-page: 111 year: 2017 ident: 672_CR7 publication-title: Eur J Pharm Sci. doi: 10.1016/j.ejps.2017.07.035 – volume: 22 start-page: 113 issue: 5 year: 2020 ident: 672_CR4 publication-title: AAPS J. doi: 10.1208/s12248-020-00495-4 – ident: 672_CR28 – volume: 23 start-page: 31 issue: 2 year: 2021 ident: 672_CR23 publication-title: AAPS J. doi: 10.1208/s12248-021-00564-2 – ident: 672_CR8 – volume: 59 start-page: 1246 issue: 2 year: 2015 ident: 672_CR30 publication-title: Antimicrob Agents Chemother. doi: 10.1128/AAC.04223-14 – volume: 22 start-page: 93 issue: 5 year: 2020 ident: 672_CR32 publication-title: AAPS J. doi: 10.1208/s12248-020-00480-x – volume: 15 start-page: 265 issue: 1-2 year: 1984 ident: 672_CR34 publication-title: Drug Metab Rev. doi: 10.3109/03602538409015066 – volume: 10 start-page: 148 issue: 1 year: 2008 ident: 672_CR18 publication-title: AAPS J. doi: 10.1208/s12248-008-9015-x – volume: 107 start-page: 250 issue: 1 year: 2018 ident: 672_CR27 publication-title: J Pharm Sci. doi: 10.1016/j.xphs.2017.08.002 – volume: 43 start-page: 485 issue: 10 year: 2005 ident: 672_CR17 publication-title: Int J Clin Pharmacol Ther. doi: 10.5414/CPP43485 – volume: 6 year: 2015 ident: 672_CR21 publication-title: Clin Transl Gastroenterol. doi: 10.1038/ctg.2015.22
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Snippet	While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs... While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs... While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs...
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SubjectTerms	Adolescent Adult Biochemistry Biological Availability Biomedical and Life Sciences Biomedicine Biotechnology Cross-Over Studies Delayed-Action Preparations Gastrointestinal Tract - physiology Humans Male Medical research Medicine, Experimental Middle Aged Models, Biological Pharmacology/Toxicology Pharmacy Physiological aspects Posaconazole Proof of Concept Study Research Article Research Design Theme: Integrating In Vitro Systems and Physiologically-Based Pharmacokinetics Modeling to Optimize Drug Product Development Therapeutic Equivalency Triazoles - administration & dosage Triazoles - pharmacokinetics Young Adult
Title	Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling
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