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  • 1.
    Darwich, Adam S.
    et al.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Margolskee, Alison
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Pepin, Xavier
    AstraZeneca, London, England;Sanofi, Paris, France.
    Aarons, Leon
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Galetin, Aleksandra
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Rostami-Hodjegan, Amin
    Univ Manchester, Manchester M13 9PL, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England.
    Carlert, Sara
    AstraZeneca, Gothenburg, Sweden.
    Hammarberg, Maria
    AstraZeneca, Gothenburg, Sweden.
    Hilgendorf, Constanze
    AstraZeneca, Gothenburg, Sweden.
    Johansson, Pernilla
    AstraZeneca, Gothenburg, Sweden.
    Karlsson, Eva
    AstraZeneca, Gothenburg, Sweden.
    Murphy, Donal
    AstraZeneca, London, England.
    Tannergren, Christer
    AstraZeneca, Gothenburg, Sweden.
    Thorn, Helena
    AstraZeneca, Gothenburg, Sweden.
    Yasin, Mohammed
    AstraZeneca, London, England.
    Mazuir, Florent
    Sanofi, Paris, France.
    Nicolas, Olivier
    Sanofi, Paris, France.
    Ramusovic, Sergej
    Sanofi, Frankfurt, Germany.
    Xu, Christine
    Sanofi, Bridgewater, NJ USA.
    Pathak, Shriram M.
    Simcyp Ltd, Sheffield, S Yorkshire, England.
    Korjamo, Timo
    Orion Pharma, Espoo, Finland.
    Laru, Johanna
    Orion Pharma, Espoo, Finland;AstraZeneca, London, England.
    Malkki, Jussi
    Orion Pharma, Espoo, Finland.
    Pappinen, Sari
    Orion Pharma, Espoo, Finland.
    Tuunainen, Johanna
    Orion Pharma, Espoo, Finland.
    Dressman, Jennifer
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Hansmann, Simone
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Kostewicz, Edmund
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    He, Handan
    Novartis, New York, NY USA.
    Heimbach, Tycho
    Novartis, New York, NY USA.
    Wu, Fan
    Novartis, New York, NY USA.
    Hoft, Carolin
    AbbVie, Wiesbaden, Germany.
    Pang, Yan
    AbbVie, Wiesbaden, Germany.
    Bolger, Michael B.
    Simulat Plus Inc, Lancaster, CA USA.
    Huehn, Eva
    Simulat Plus Inc, Lancaster, CA USA.
    Lukacova, Viera
    Simulat Plus Inc, Lancaster, CA USA.
    Mullin, James M.
    Simulat Plus Inc, Lancaster, CA USA.
    Szeto, Ke X.
    Simulat Plus Inc, Lancaster, CA USA.
    Costales, Chester
    Pfizer, New York, NY USA.
    Lin, Jian
    Pfizer, New York, NY USA.
    McAllister, Mark
    Pfizer, Tadworth, Middx, England.
    Modi, Sweta
    Pfizer, New York, NY USA.
    Rotter, Charles
    Pfizer, New York, NY USA.
    Varma, Manthena
    Pfizer, Tadworth, Middx, England.
    Wong, Mei
    Pfizer, Tadworth, Middx, England.
    Mitra, Amitava
    Merck Sharp & Dohme Ltd, Hoddesdon, Herts, England.
    Bevernage, Jan
    Janssen, Beerse, Belgium.
    Biewenga, Jeike
    Janssen, Beerse, Belgium.
    Van Peer, Achiel
    Janssen, Beerse, Belgium.
    Lloyd, Richard
    GlaxoSmithKline, Brentford, Middx, England.
    Shardlow, Carole
    GlaxoSmithKline, Brentford, Middx, England.
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Mishenzon, Irina
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Nguyen, Mai Anh
    Brown, Jonathan
    Bristol Myers Squibb, Uxbridge, Middx, England.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    AstraZeneca, Gothenburg, Sweden.
    IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 96, p. 626-642Article in journal (Refereed)
    Abstract [en]

    Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.

  • 2.
    Margolskee, Alison
    et al.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Darwich, Adam S.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Pepin, Xavier
    AstraZeneca, London, England;Sanofi, Paris, France.
    Aarons, Leon
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Galetin, Aleksandra
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Rostami-Hodjegan, Amin
    Univ Manchester, Manchester M13 9PL, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England.
    Carlert, Sara
    AstraZeneca, Gothenburg, Sweden.
    Hammarberg, Maria
    AstraZeneca, Gothenburg, Sweden.
    Hilgendorf, Constanze
    AstraZeneca, Gothenburg, Sweden.
    Johansson, Pernilla
    AstraZeneca, Gothenburg, Sweden.
    Karlsson, Eva
    AstraZeneca, Gothenburg, Sweden.
    Murphy, Donal
    AstraZeneca, London, England.
    Tannergren, Christer
    AstraZeneca, Gothenburg, Sweden.
    Thorn, Helena
    AstraZeneca, Gothenburg, Sweden.
    Yasin, Mohammed
    AstraZeneca, London, England.
    Mazuir, Florent
    Sanofi, Paris, France.
    Nicolas, Olivier
    Sanofi, Paris, France.
    Ramusovic, Sergej
    Sanofi, Frankfurt, Germany.
    Xu, Christine
    Sanofi, Bridgewater, NJ USA.
    Pathak, Shriram M.
    Korjamo, Timo
    Orion Pharma, Espoo, Finland.
    Laru, Johanna
    Orion Pharma, Espoo, Finland;AstraZeneca, London, England.
    Malkki, Jussi
    Orion Pharma, Espoo, Finland.
    Pappinen, Sari
    Orion Pharma, Espoo, Finland.
    Tuunainen, Johanna
    Orion Pharma, Espoo, Finland.
    Dressman, Jennifer
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Hansmanni, Simone
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Kostewicz, Edmund
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    He, Handan
    Novartis, New York, NY USA.
    Heimbach, Tycho
    Novartis, New York, NY USA.
    Wu, Fan
    Novartis, New York, NY USA.
    Hoft, Carolin
    AbbVie, Wiesbaden, Germany.
    Laplanche, Loic
    AbbVie, Wiesbaden, Germany.
    Pang, Yan
    AbbVie, Wiesbaden, Germany.
    Bolger, Michael B.
    Simulat Plus Inc, Lancaster, CA USA.
    Huehn, Eva
    Simulat Plus Inc, Lancaster, CA USA.
    Lukacova, Viera
    Simulat Plus Inc, Lancaster, CA USA.
    Mullin, James M.
    Simulat Plus Inc, Lancaster, CA USA.
    Szeto, Ke X.
    Simulat Plus Inc, Lancaster, CA USA.
    Costales, Chester
    Pfizer, New York, NY USA.
    Lin, Jian
    Pfizer, New York, NY USA.
    McAllister, Mark
    Pfizer, Tadworth, England.
    Modi, Sweta
    Pfizer, New York, NY USA.
    Rotter, Charles
    Pfizer, New York, NY USA.
    Varma, Manthena
    Pfizer, Tadworth, England.
    Wong, Mei
    Pfizer, Tadworth, England.
    Mitra, Amitava
    Merck Sharp & Dohme Ltd, Hoddesdon, Herts, England.
    Bevernage, Jan
    Janssen, Beerse, Belgium.
    Biewenga, Jeike
    Janssen, Beerse, Belgium.
    Van Peer, Achiel
    Janssen, Beerse, Belgium.
    Lloyd, Richard
    GlaxoSmithKline, Brentford, Middx, England.
    Shardlow, Carole
    GlaxoSmithKline, Brentford, Middx, England.
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Mishenzon, Irina
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Nguyen, Mai Anh
    Brown, Jonathan
    Bristol Myers Squibb, Uxbridge, Middx, England.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    AstraZeneca, Gothenburg, Sweden.
    IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 96, p. 610-625Article in journal (Refereed)
    Abstract [en]

    Orally administered drugs are subject to a number of barriers impacting bioavailability (F-oral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp (R), and GastroPlus (TM)) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, F-oral and relative AUC (F-rel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.

1 - 2 of 2
CiteExportLink to result list
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Cite
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  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
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Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf