A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies
Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and neces...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Yuan, Dongfen [verfasserIn] |
|---|
| Format: |
E-Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2019transfer abstract |
|---|
| Übergeordnetes Werk: |
Enthalten in: The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms - Heyden, Mariano L.M. ELSEVIER, 2022, official journal of the European Federation for Pharmaceutical Sciences, New York, NY [u.a.] |
|---|---|
| Übergeordnetes Werk: |
volume:138 ; year:2019 ; day:1 ; month:10 ; pages:0 |
| Links: |
|---|
| DOI / URN: |
10.1016/j.ejps.2019.105032 |
|---|
| Katalog-ID: |
ELV047685964 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | ELV047685964 | ||
| 003 | DE-627 | ||
| 005 | 20230626020201.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 191022s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ejps.2019.105032 |2 doi | |
| 028 | 5 | 2 | |a GBV00000000000725.pica |
| 035 | |a (DE-627)ELV047685964 | ||
| 035 | |a (ELSEVIER)S0928-0987(19)30296-9 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | 4 | |a 300 |a 330 |a 360 |q VZ |
| 084 | |a 85.05 |2 bkl | ||
| 084 | |a 85.06 |2 bkl | ||
| 084 | |a 89.52 |2 bkl | ||
| 100 | 1 | |a Yuan, Dongfen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies |
| 264 | 1 | |c 2019transfer abstract | |
| 336 | |a nicht spezifiziert |b zzz |2 rdacontent | ||
| 337 | |a nicht spezifiziert |b z |2 rdamedia | ||
| 338 | |a nicht spezifiziert |b zu |2 rdacarrier | ||
| 520 | |a Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. | ||
| 520 | |a Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. | ||
| 700 | 1 | |a Rode, Frederik |4 oth | |
| 700 | 1 | |a Cao, Yanguang |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |n Elsevier |a Heyden, Mariano L.M. ELSEVIER |t The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms |d 2022 |d official journal of the European Federation for Pharmaceutical Sciences |g New York, NY [u.a.] |w (DE-627)ELV009954198 |
| 773 | 1 | 8 | |g volume:138 |g year:2019 |g day:1 |g month:10 |g pages:0 |
| 856 | 4 | 0 | |u https://doi.org/10.1016/j.ejps.2019.105032 |3 Volltext |
| 912 | |a GBV_USEFLAG_U | ||
| 912 | |a GBV_ELV | ||
| 912 | |a SYSFLAG_U | ||
| 936 | b | k | |a 85.05 |j Betriebssoziologie |j Betriebspsychologie |q VZ |
| 936 | b | k | |a 85.06 |j Unternehmensführung |q VZ |
| 936 | b | k | |a 89.52 |j Politische Psychologie |j Politische Soziologie |q VZ |
| 951 | |a AR | ||
| 952 | |d 138 |j 2019 |b 1 |c 1001 |h 0 | ||
| author_variant |
d y dy |
|---|---|
| matchkey_str |
yuandongfenrodefrederikcaoyanguang:2019----:sseshraoieipamcdnmcoefroczmboxlrteoetao |
| hierarchy_sort_str |
2019transfer abstract |
| bklnumber |
85.05 85.06 89.52 |
| publishDate |
2019 |
| allfields |
10.1016/j.ejps.2019.105032 doi GBV00000000000725.pica (DE-627)ELV047685964 (ELSEVIER)S0928-0987(19)30296-9 DE-627 ger DE-627 rakwb eng 300 330 360 VZ 85.05 bkl 85.06 bkl 89.52 bkl Yuan, Dongfen verfasserin aut A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies 2019transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Rode, Frederik oth Cao, Yanguang oth Enthalten in Elsevier Heyden, Mariano L.M. ELSEVIER The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms 2022 official journal of the European Federation for Pharmaceutical Sciences New York, NY [u.a.] (DE-627)ELV009954198 volume:138 year:2019 day:1 month:10 pages:0 https://doi.org/10.1016/j.ejps.2019.105032 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 85.05 Betriebssoziologie Betriebspsychologie VZ 85.06 Unternehmensführung VZ 89.52 Politische Psychologie Politische Soziologie VZ AR 138 2019 1 1001 0 |
| spelling |
10.1016/j.ejps.2019.105032 doi GBV00000000000725.pica (DE-627)ELV047685964 (ELSEVIER)S0928-0987(19)30296-9 DE-627 ger DE-627 rakwb eng 300 330 360 VZ 85.05 bkl 85.06 bkl 89.52 bkl Yuan, Dongfen verfasserin aut A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies 2019transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Rode, Frederik oth Cao, Yanguang oth Enthalten in Elsevier Heyden, Mariano L.M. ELSEVIER The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms 2022 official journal of the European Federation for Pharmaceutical Sciences New York, NY [u.a.] (DE-627)ELV009954198 volume:138 year:2019 day:1 month:10 pages:0 https://doi.org/10.1016/j.ejps.2019.105032 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 85.05 Betriebssoziologie Betriebspsychologie VZ 85.06 Unternehmensführung VZ 89.52 Politische Psychologie Politische Soziologie VZ AR 138 2019 1 1001 0 |
| allfields_unstemmed |
10.1016/j.ejps.2019.105032 doi GBV00000000000725.pica (DE-627)ELV047685964 (ELSEVIER)S0928-0987(19)30296-9 DE-627 ger DE-627 rakwb eng 300 330 360 VZ 85.05 bkl 85.06 bkl 89.52 bkl Yuan, Dongfen verfasserin aut A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies 2019transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Rode, Frederik oth Cao, Yanguang oth Enthalten in Elsevier Heyden, Mariano L.M. ELSEVIER The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms 2022 official journal of the European Federation for Pharmaceutical Sciences New York, NY [u.a.] (DE-627)ELV009954198 volume:138 year:2019 day:1 month:10 pages:0 https://doi.org/10.1016/j.ejps.2019.105032 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 85.05 Betriebssoziologie Betriebspsychologie VZ 85.06 Unternehmensführung VZ 89.52 Politische Psychologie Politische Soziologie VZ AR 138 2019 1 1001 0 |
| allfieldsGer |
10.1016/j.ejps.2019.105032 doi GBV00000000000725.pica (DE-627)ELV047685964 (ELSEVIER)S0928-0987(19)30296-9 DE-627 ger DE-627 rakwb eng 300 330 360 VZ 85.05 bkl 85.06 bkl 89.52 bkl Yuan, Dongfen verfasserin aut A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies 2019transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Rode, Frederik oth Cao, Yanguang oth Enthalten in Elsevier Heyden, Mariano L.M. ELSEVIER The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms 2022 official journal of the European Federation for Pharmaceutical Sciences New York, NY [u.a.] (DE-627)ELV009954198 volume:138 year:2019 day:1 month:10 pages:0 https://doi.org/10.1016/j.ejps.2019.105032 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 85.05 Betriebssoziologie Betriebspsychologie VZ 85.06 Unternehmensführung VZ 89.52 Politische Psychologie Politische Soziologie VZ AR 138 2019 1 1001 0 |
| allfieldsSound |
10.1016/j.ejps.2019.105032 doi GBV00000000000725.pica (DE-627)ELV047685964 (ELSEVIER)S0928-0987(19)30296-9 DE-627 ger DE-627 rakwb eng 300 330 360 VZ 85.05 bkl 85.06 bkl 89.52 bkl Yuan, Dongfen verfasserin aut A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies 2019transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. Rode, Frederik oth Cao, Yanguang oth Enthalten in Elsevier Heyden, Mariano L.M. ELSEVIER The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms 2022 official journal of the European Federation for Pharmaceutical Sciences New York, NY [u.a.] (DE-627)ELV009954198 volume:138 year:2019 day:1 month:10 pages:0 https://doi.org/10.1016/j.ejps.2019.105032 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 85.05 Betriebssoziologie Betriebspsychologie VZ 85.06 Unternehmensführung VZ 89.52 Politische Psychologie Politische Soziologie VZ AR 138 2019 1 1001 0 |
| language |
English |
| source |
Enthalten in The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms New York, NY [u.a.] volume:138 year:2019 day:1 month:10 pages:0 |
| sourceStr |
Enthalten in The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms New York, NY [u.a.] volume:138 year:2019 day:1 month:10 pages:0 |
| format_phy_str_mv |
Article |
| bklname |
Betriebssoziologie Betriebspsychologie Unternehmensführung Politische Psychologie Politische Soziologie |
| institution |
findex.gbv.de |
| dewey-raw |
300 |
| isfreeaccess_bool |
false |
| container_title |
The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms |
| authorswithroles_txt_mv |
Yuan, Dongfen @@aut@@ Rode, Frederik @@oth@@ Cao, Yanguang @@oth@@ |
| publishDateDaySort_date |
2019-01-01T00:00:00Z |
| hierarchy_top_id |
ELV009954198 |
| dewey-sort |
3300 |
| id |
ELV047685964 |
| language_de |
englisch |
| fullrecord |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">ELV047685964</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230626020201.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">191022s2019 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.ejps.2019.105032</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">GBV00000000000725.pica</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)ELV047685964</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(ELSEVIER)S0928-0987(19)30296-9</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">300</subfield><subfield code="a">330</subfield><subfield code="a">360</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">85.05</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">85.06</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">89.52</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Yuan, Dongfen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2019transfer abstract</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zzz</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">z</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zu</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies.</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rode, Frederik</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Cao, Yanguang</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="n">Elsevier</subfield><subfield code="a">Heyden, Mariano L.M. ELSEVIER</subfield><subfield code="t">The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms</subfield><subfield code="d">2022</subfield><subfield code="d">official journal of the European Federation for Pharmaceutical Sciences</subfield><subfield code="g">New York, NY [u.a.]</subfield><subfield code="w">(DE-627)ELV009954198</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:138</subfield><subfield code="g">year:2019</subfield><subfield code="g">day:1</subfield><subfield code="g">month:10</subfield><subfield code="g">pages:0</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1016/j.ejps.2019.105032</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ELV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_U</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">85.05</subfield><subfield code="j">Betriebssoziologie</subfield><subfield code="j">Betriebspsychologie</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">85.06</subfield><subfield code="j">Unternehmensführung</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">89.52</subfield><subfield code="j">Politische Psychologie</subfield><subfield code="j">Politische Soziologie</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">138</subfield><subfield code="j">2019</subfield><subfield code="b">1</subfield><subfield code="c">1001</subfield><subfield code="h">0</subfield></datafield></record></collection>
|
| author |
Yuan, Dongfen |
| spellingShingle |
Yuan, Dongfen ddc 300 bkl 85.05 bkl 85.06 bkl 89.52 A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies |
| authorStr |
Yuan, Dongfen |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)ELV009954198 |
| format |
electronic Article |
| dewey-ones |
300 - Social sciences 330 - Economics 360 - Social problems & services; associations |
| delete_txt_mv |
keep |
| author_role |
aut |
| collection |
elsevier |
| remote_str |
true |
| illustrated |
Not Illustrated |
| topic_title |
300 330 360 VZ 85.05 bkl 85.06 bkl 89.52 bkl A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies |
| topic |
ddc 300 bkl 85.05 bkl 85.06 bkl 89.52 |
| topic_unstemmed |
ddc 300 bkl 85.05 bkl 85.06 bkl 89.52 |
| topic_browse |
ddc 300 bkl 85.05 bkl 85.06 bkl 89.52 |
| format_facet |
Elektronische Aufsätze Aufsätze Elektronische Ressource |
| format_main_str_mv |
Text Zeitschrift/Artikel |
| carriertype_str_mv |
zu |
| author2_variant |
f r fr y c yc |
| hierarchy_parent_title |
The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms |
| hierarchy_parent_id |
ELV009954198 |
| dewey-tens |
300 - Social sciences, sociology & anthropology 330 - Economics 360 - Social problems & social services |
| hierarchy_top_title |
The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms |
| isfreeaccess_txt |
false |
| familylinks_str_mv |
(DE-627)ELV009954198 |
| title |
A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies |
| ctrlnum |
(DE-627)ELV047685964 (ELSEVIER)S0928-0987(19)30296-9 |
| title_full |
A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies |
| author_sort |
Yuan, Dongfen |
| journal |
The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms |
| journalStr |
The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms |
| lang_code |
eng |
| isOA_bool |
false |
| dewey-hundreds |
300 - Social sciences |
| recordtype |
marc |
| publishDateSort |
2019 |
| contenttype_str_mv |
zzz |
| container_start_page |
0 |
| author_browse |
Yuan, Dongfen |
| container_volume |
138 |
| class |
300 330 360 VZ 85.05 bkl 85.06 bkl 89.52 bkl |
| format_se |
Elektronische Aufsätze |
| author-letter |
Yuan, Dongfen |
| doi_str_mv |
10.1016/j.ejps.2019.105032 |
| dewey-full |
300 330 360 |
| title_sort |
a systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-tfpi recycling antibodies |
| title_auth |
A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies |
| abstract |
Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. |
| abstractGer |
Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. |
| abstract_unstemmed |
Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies. |
| collection_details |
GBV_USEFLAG_U GBV_ELV SYSFLAG_U |
| title_short |
A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies |
| url |
https://doi.org/10.1016/j.ejps.2019.105032 |
| remote_bool |
true |
| author2 |
Rode, Frederik Cao, Yanguang |
| author2Str |
Rode, Frederik Cao, Yanguang |
| ppnlink |
ELV009954198 |
| mediatype_str_mv |
z |
| isOA_txt |
false |
| hochschulschrift_bool |
false |
| author2_role |
oth oth |
| doi_str |
10.1016/j.ejps.2019.105032 |
| up_date |
2024-07-06T16:49:36.073Z |
| _version_ |
1803849119644516352 |
| fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">ELV047685964</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230626020201.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">191022s2019 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.ejps.2019.105032</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">GBV00000000000725.pica</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)ELV047685964</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(ELSEVIER)S0928-0987(19)30296-9</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">300</subfield><subfield code="a">330</subfield><subfield code="a">360</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">85.05</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">85.06</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">89.52</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Yuan, Dongfen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2019transfer abstract</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zzz</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">z</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zu</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies.</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rode, Frederik</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Cao, Yanguang</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="n">Elsevier</subfield><subfield code="a">Heyden, Mariano L.M. ELSEVIER</subfield><subfield code="t">The face of wrongdoing? An expectancy violations perspective on CEO facial characteristics and media coverage of misconducting firms</subfield><subfield code="d">2022</subfield><subfield code="d">official journal of the European Federation for Pharmaceutical Sciences</subfield><subfield code="g">New York, NY [u.a.]</subfield><subfield code="w">(DE-627)ELV009954198</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:138</subfield><subfield code="g">year:2019</subfield><subfield code="g">day:1</subfield><subfield code="g">month:10</subfield><subfield code="g">pages:0</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1016/j.ejps.2019.105032</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ELV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_U</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">85.05</subfield><subfield code="j">Betriebssoziologie</subfield><subfield code="j">Betriebspsychologie</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">85.06</subfield><subfield code="j">Unternehmensführung</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">89.52</subfield><subfield code="j">Politische Psychologie</subfield><subfield code="j">Politische Soziologie</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">138</subfield><subfield code="j">2019</subfield><subfield code="b">1</subfield><subfield code="c">1001</subfield><subfield code="h">0</subfield></datafield></record></collection>
|
| score |
7.4007034 |