{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:44:20Z","timestamp":1790077460377,"version":"4.0.1"},"reference-count":22,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Modakafusp alfa (TAK\u2010573) is a novel, first\u2010in\u2010class fusion protein of a humanized anti\u2010CD38 IgG4 kappa antibody fused to attenuated human interferon alfa\u20102b. It acts as an agonistic innate immunity enhancer through targeted interferon (IFN) signaling and has been investigated as an immune\u2010oncology therapeutic agent in patients with relapsed\/refractory multiple myeloma (RRMM). Population PK analysis and sequential PK\u2010PD analysis of serum M\u2010protein (MP) as a primary marker of tumor burden in RRMM were conducted using dose escalation (Part 1) and dose expansion (Part 2) data from 96 RRMM patients enrolled in the Phase 1\/2 iinnovate\u20101 trial. After exploring various structural PK models with different levels of mechanistic complexity, a Michaelis\u2013Menten approximation model that included an anti\u2010drug antibody (ADA) binding model adequately captured the nonlinear PK of modakafusp alfa and the apparent time\u2010varying impact of ADA on the PK. Body weight was a significant predictor of central volume of distribution (exponent of 0.51) but was not predictive of elimination\u2010related parameters given both catabolic and likely target\u2010mediated elimination processes. Serum MP data from patients evaluable at baseline were adequately characterized using the Claret tumor growth inhibition and drug resistance model, with antitumor drug effect using an E\n                    <jats:sub>max<\/jats:sub>\n                    model. The population PK and PK\u2010PD modeling results supported model\u2010informed drug development for modakafusp alfa, including the switch from weight\u2010based to fixed dosing and the selection of two fixed doses for the randomized dose extension (Part 3) phase of the trial to inform future optimal dose selection, which is consistent with the Project Optimus paradigm.\n                  <\/jats:p>","DOI":"10.1111\/cts.70296","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T08:10:16Z","timestamp":1753085416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Population Pharmacokinetic and Pharmacokinetic\u2010Pharmacodynamic Modeling of Serum M\u2010Protein Response for Modakafusp Alfa in a Phase 1\/2 Study of Patients With Relapsed or Refractory Multiple Myeloma"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5615-8046","authenticated-orcid":false,"given":"Cheryl","family":"Li","sequence":"first","affiliation":[{"name":"Quantitative Clinical Pharmacology Takeda Development Center Americas, Inc. (TDCA)  Lexington Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0384-9320","authenticated-orcid":false,"given":"Andrew","family":"Santulli","sequence":"additional","affiliation":[{"name":"Enhanced Pharmacodynamics, LLC  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8986-2250","authenticated-orcid":false,"given":"Scott","family":"Van Wart","sequence":"additional","affiliation":[{"name":"Enhanced Pharmacodynamics, LLC  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8031-6408","authenticated-orcid":false,"given":"Lili","family":"Yang","sequence":"additional","affiliation":[{"name":"Translational Biomarkers and Bioanalytics Takeda Development Center Americas, Inc. (TDCA)  Lexington Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8776-1533","authenticated-orcid":false,"given":"Kaveri","family":"Suryanarayan","sequence":"additional","affiliation":[{"name":"Clinical Science Takeda Development Center Americas, Inc. (TDCA)  Lexington Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8612-882X","authenticated-orcid":false,"given":"Sarah F.","family":"Cook","sequence":"additional","affiliation":[{"name":"Enhanced Pharmacodynamics, LLC  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0250-3950","authenticated-orcid":false,"given":"Xavier","family":"Parot","sequence":"additional","affiliation":[{"name":"Clinical Science Takeda Development Center Americas, Inc. 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