PK/PD and Bioanalytical Considerations of AAV-Based Gene Therapies : an IQ Consortium Industry Position Paper
© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists..
Interest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist. This position paper comes from the Novel Modalities Working Group (WG), part of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). The pan-industry WG effort focuses on the nonclinical PK and clinical pharmacology aspects of AAV gene therapy and related bioanalytical considerations.Traditional PK concepts are generally not applicable to AAV-based therapies due to the inherent complexity of a transgene-carrying viral vector, and the multiple steps and analytes involved in cell transduction and transgene-derived protein expression. Therefore, we explain PK concepts of biodistribution of AAV-based therapies and place key terminologies related to drug exposure and PD in the proper context. Factors affecting biodistribution are presented in detail, and guidelines are provided to design nonclinical studies to enable a stage-gated progression to Phase 1 testing. The nonclinical and clinical utility of transgene DNA, mRNA, and protein analytes are discussed with bioanalytical strategies to measure these analytes. The pros and cons of qPCR vs. ddPCR technologies for DNA/RNA measurement and qualitative vs. quantitative methods for transgene-derived protein are also presented. Last, best practices and recommendations for use of clinical and nonclinical data to project human dose and response are discussed. Together, the manuscript provides a holistic framework to discuss evolving concepts of PK/PD modeling, bioanalytical technologies, and clinical dose selection in gene therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
The AAPS journal - 25(2023), 5 vom: 31. Juli, Seite 78 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kavita, Uma [VerfasserIn] |
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| Links: |
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| Themen: |
Adeno-associated virus |
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| Anmerkungen: |
Date Completed 01.08.2023 Date Revised 22.09.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1208/s12248-023-00842-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM360229018 |
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| 520 | |a © 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists. | ||
| 520 | |a Interest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist. This position paper comes from the Novel Modalities Working Group (WG), part of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). The pan-industry WG effort focuses on the nonclinical PK and clinical pharmacology aspects of AAV gene therapy and related bioanalytical considerations.Traditional PK concepts are generally not applicable to AAV-based therapies due to the inherent complexity of a transgene-carrying viral vector, and the multiple steps and analytes involved in cell transduction and transgene-derived protein expression. Therefore, we explain PK concepts of biodistribution of AAV-based therapies and place key terminologies related to drug exposure and PD in the proper context. Factors affecting biodistribution are presented in detail, and guidelines are provided to design nonclinical studies to enable a stage-gated progression to Phase 1 testing. The nonclinical and clinical utility of transgene DNA, mRNA, and protein analytes are discussed with bioanalytical strategies to measure these analytes. The pros and cons of qPCR vs. ddPCR technologies for DNA/RNA measurement and qualitative vs. quantitative methods for transgene-derived protein are also presented. Last, best practices and recommendations for use of clinical and nonclinical data to project human dose and response are discussed. Together, the manuscript provides a holistic framework to discuss evolving concepts of PK/PD modeling, bioanalytical technologies, and clinical dose selection in gene therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Review | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a adeno-associated virus | |
| 650 | 4 | |a bioanalytical methodologies | |
| 650 | 4 | |a gene therapy | |
| 650 | 4 | |a pharmacodynamics | |
| 650 | 4 | |a pharmacokinetics | |
| 700 | 1 | |a Sun, Kefeng |e verfasserin |4 aut | |
| 700 | 1 | |a Braun, Manuela |e verfasserin |4 aut | |
| 700 | 1 | |a Lembke, Wibke |e verfasserin |4 aut | |
| 700 | 1 | |a Mody, Hardik |e verfasserin |4 aut | |
| 700 | 1 | |a Kamerud, John |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Tong-Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Braun, Inka V |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Xiaodong |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Swati |e verfasserin |4 aut | |
| 700 | 1 | |a Hofer, Magdalena |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Michael Z |e verfasserin |4 aut | |
| 700 | 1 | |a Loo, LiNa |e verfasserin |4 aut | |
| 700 | 1 | |a McBlane, Fraser |e verfasserin |4 aut | |
| 700 | 1 | |a Menochet, Karelle |e verfasserin |4 aut | |
| 700 | 1 | |a Stubenrauch, Kay-Gunnar |e verfasserin |4 aut | |
| 700 | 1 | |a Upreti, Vijay V |e verfasserin |4 aut | |
| 700 | 1 | |a Vigil, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Wiethoff, Christopher M |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Cindy Q |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Jawa, Vibha |e verfasserin |4 aut | |
| 700 | 1 | |a Chemuturi, Nagendra |e verfasserin |4 aut | |
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