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Interspecies normalization of dose response relationship for adeno-associated virus-mediated hemophilia gene therapy -- application to first-in-human dose prediction
  • Peng Zou
Peng Zou
Daiichi Sankyo Inc

Corresponding Author:[email protected]

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Establishing dose response relationships in targeted patients is foundational in the development of therapeutic drugs including gene therapy products. Enlightened by interspecies normalization of plasma drug concentration-time curves using Dedrick plot, the author of this manuscript first demonstrated the feasibility of normalizing dose-response relationship of adeno-associated virus (AAV)-mediated hemophilia gene therapy products in multiple species to a species-invariant scale. Preclinical dose-response relationships of eight AAV vectors were normalized using an exponent of 0.25 and applied to first-in-human (FIH) dose prediction. The performance of this dose-response normalization approach for FIH dose prediction was compared to that of direct body weight-based dose conversion and allometric scaling approaches. The study results suggested that in addition to hemophilia dogs and non-human primates, inclusion of larger animal models (e.g., swine and cattle) in preclinical dose-finding studies of AAV vectors might improve the performance of interspecies dose-response normalization approach. Furthermore, it was found that AAV capsid-specific T cell responses in hemophilia patients might cause underprediction of FIH dose while novel bioengineered capsids with a high transduction efficiency specifically in human hepatocytes might cause overprediction of FIH dose. These factors should be considered when dose-response is extrapolated from preclinical species to patients.
11 Jul 2022Submitted to British Journal of Clinical Pharmacology
12 Jul 2022Submission Checks Completed
12 Jul 2022Assigned to Editor
03 Aug 2022Reviewer(s) Assigned
26 Aug 2022Review(s) Completed, Editorial Evaluation Pending
13 Sep 2022Editorial Decision: Revise Minor
14 Sep 20221st Revision Received
15 Sep 2022Submission Checks Completed
15 Sep 2022Assigned to Editor
15 Sep 2022Review(s) Completed, Editorial Evaluation Pending
19 Sep 2022Reviewer(s) Assigned
10 Oct 2022Editorial Decision: Revise Major
12 Oct 20222nd Revision Received
13 Oct 2022Submission Checks Completed
13 Oct 2022Assigned to Editor
13 Oct 2022Review(s) Completed, Editorial Evaluation Pending
13 Oct 2022Reviewer(s) Assigned
31 Oct 2022Editorial Decision: Revise Minor
01 Nov 20223rd Revision Received
01 Nov 2022Submission Checks Completed
01 Nov 2022Assigned to Editor
01 Nov 2022Review(s) Completed, Editorial Evaluation Pending
08 Nov 2022Editorial Decision: Accept
11 Nov 2022Published in British Journal of Clinical Pharmacology. 10.1111/bcp.15597