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Posdinemab (JNJ\u201063733657), a humanized IgG1\/kappa monoclonal antibody that targets phosphorylated Tau protein at amino acid 217 (p217+tau), is currently in clinical development for the treatment of AD. In a first\u2010in\u2010human Phase 1 study (NCT03375697), posdinemab was well tolerated at doses up to 60\u2009mg\/kg, demonstrated linear pharmacokinetics (PK) in serum, and induced dose\u2010dependent reductions in p217+tau levels in cerebrospinal fluid (CSF). The objective of the current analysis was to develop a mechanism\u2010based population pharmacokinetic\u2013pharmacodynamic (popPK\u2010PD) model to guide the Phase 2 (Au\u03c4onomy) dose selection of posdinemab in participants with AD using the Phase 1 data from 69 adults. A two\u2010compartment model was selected, which successfully described the available clinical PK\u2013PD data and demonstrated that posdinemab PK in serum is linear, dose\u2010proportional, and time\u2010independent. Suppression of free p217+tau in CSF was used to reflect free antibody available to bind tau seeds in interstitial fluid (ISF). The PK\u2013PD model\u2010based simulations for fixed intravenous doses of 1,000\u2009mg and 3,000\u2009mg every 4\u2009weeks predicted &gt;90% reduction in tau seeds in ISF by Day 391 and Day 154, respectively, following treatment initiation. This model provides a physiologically relevant simulation\u2010framework to investigate the impact of various posdinemab dose levels on PK\u2013PD profiles, thereby supporting the clinical trial design of the Au\u03c4onomy study (NCT04619420).<\/jats:p>","DOI":"10.1002\/cpt.70173","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T06:53:21Z","timestamp":1766472801000},"page":"979-989","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanistic Population Pharmacokinetic\u2013Pharmacodynamic Model of the Tau\u2010Targeted Antibody Posdinemab in Healthy Participants and Participants with Alzheimer\u2019s Disease"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0963-2971","authenticated-orcid":false,"given":"Carlos","family":"P\u00e9rez\u2010Ruixo","sequence":"first","affiliation":[{"name":"Johnson &amp; Johnson, Clinical Pharmacology &amp; Pharmacometrics  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjue","family":"Li","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson, Clinical Pharmacology &amp; Pharmacometrics  Titusville New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy R.","family":"Galpern","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson, Neuroscience Clinical Development  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-745X","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"Perez\u2010Ruixo","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson, Clinical Pharmacology &amp; Pharmacometrics  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(21)00249-8"},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01911-3"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-023-01349-9"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-02087-9"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(22)00168-5"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-023-01321-7"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2100708"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30480-6"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207663"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00523-w"},{"key":"e_1_2_11_12_1","unstructured":"Barton M.et al.Results from TOGETHER a double\u2010blind placebo\u2010controlled Phase II study evaluating efficacy safety and tolerability of bepranemab in prodromal\u2013mild AD. 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