A mechanistic assessment of the nature of pharmacodynamic drug-drug interaction in vivo and in vitro
Abstract Combination pharmacotherapy is becoming increasingly necessary because most diseases are pathophysiologically controlled at the subcellular level by target proteins in a combinatorial manner. We demonstrate the application of the stimulus–response mechanistic model in characterising the drug and physiological properties of pharmacodynamic drug-drug interactions (PDDI) using previously published in vitro and in vivo drug combination experiments. The in vitro experiment tested the effect of a combination of SCH66336 and 4-HPR on the survival of in squamous cell carcinoma cell lines, while the in vivo experiment tested the effect of a combination of cetuximab and cisplatin on tumour growth inhibition in female xenograft mice. The model adequately described both experiments, quantified both system and drug properties and predicted the nature of the PDDI mechanism. Strong baseline signals of 7.35 and 610 units existed in the in vitro and in vivo experiments respectively. An overall synergistic relationship (interaction index = 1.03E-8) was detected in the in vitro experiment. In the in vivo model, the overall interaction index was 70,139.45 implying an antagonistic interaction between the cisplatin and the cetuximab signals..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
In Silico Pharmacology - 11(2023), 1 vom: 27. Okt. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bisaso, Kuteesa R. [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Combination therapy |
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| Anmerkungen: |
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s40203-023-00168-y |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abstract Combination pharmacotherapy is becoming increasingly necessary because most diseases are pathophysiologically controlled at the subcellular level by target proteins in a combinatorial manner. We demonstrate the application of the stimulus–response mechanistic model in characterising the drug and physiological properties of pharmacodynamic drug-drug interactions (PDDI) using previously published in vitro and in vivo drug combination experiments. The in vitro experiment tested the effect of a combination of SCH66336 and 4-HPR on the survival of in squamous cell carcinoma cell lines, while the in vivo experiment tested the effect of a combination of cetuximab and cisplatin on tumour growth inhibition in female xenograft mice. The model adequately described both experiments, quantified both system and drug properties and predicted the nature of the PDDI mechanism. Strong baseline signals of 7.35 and 610 units existed in the in vitro and in vivo experiments respectively. An overall synergistic relationship (interaction index = 1.03E-8) was detected in the in vitro experiment. In the in vivo model, the overall interaction index was 70,139.45 implying an antagonistic interaction between the cisplatin and the cetuximab signals. | ||
| 650 | 4 | |a Pharmacodynamic drug-drug interactions |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Mukonzo, Jackson K. |4 aut | |
| 700 | 1 | |a Ette, Ene I. |4 aut | |
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