{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:34:00Z","timestamp":1788932040147,"version":"build-2803163510"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T00:00:00Z","timestamp":1669420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>The aim of this study is to develop an approach to predict human dose\u2013response relationship and first\u2010in\u2010human (FIH) dose for adeno\u2010associated virus (AAV)\u2010mediated haemophilia gene therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Preclinical dose\u2013response relationships of 7 AAV vectors were normalized to a species\u2010invariant scale using an exponent of 0.25, and the normalized dose\u2013response relationship was then used for FIH dose prediction. The performance of this dose\u2013response normalization approach for FIH dose prediction was compared to that of direct body weight\u2010based dose (vg\/kg) conversion and allometric scaling approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A power regression analysis of normalized factor VIII (FVIII) or factor IX (FIX) showed a moderate\u2010to\u2010strong correlation between FVIII or FIX and vector dose across 3 species (\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      ranged 0.59 to 0.89), indicating it was feasible to normalize dose\u2013response in multiple species to a species\u2010invariant scale. When the mean values of normalized FVIII or FIX at each dose level were used for regression, the\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      values of the 7 vectors were improved to be &gt;0.84. The FIH doses predicted by the 3 approaches were ranked as allometric scaling &gt; dose\u2013response normalization &gt; direct vg\/kg conversion for all vectors except for rAAV2\u2010hAAT\u2010FIX and scAAV2\/8\u2010LP1\u2010hFIXco. Among the 7 vectors, dose\u2013response normalization, direct vg\/kg conversion and allometric scaling generated accurate FIH dose predictions for 2, 2 and 3 vectors, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study first demonstrated that it is feasible to normalize dose\u2013response relationship of AAV\u2010mediated haemophilia gene therapy in multiple species to a species\u2010invariant scale. The normalized dose\u2010response relationship from preclinical species was successfully extrapolated to patients for FIH dose prediction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bcp.15597","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T09:34:35Z","timestamp":1668159275000},"page":"1393-1401","source":"Crossref","is-referenced-by-count":6,"title":["Interspecies normalization of dose\u2010response relationship for adeno\u2010associated virus\u2010mediated haemophilia gene therapy\u2014Application to human dose prediction"],"prefix":"10.1111","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0416-2731","authenticated-orcid":false,"given":"Peng","family":"Zou","sequence":"first","affiliation":[{"name":"Quantitative Clinical Pharmacology Daiichi Sankyo, Inc.  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