{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:16:44Z","timestamp":1790651804186,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenias, hypercellular bone marrow, and dysplastic hematopoietic progenitors. MDS remains a challenge to treat due to the complex interplay between disease\u2010induced and treatment\u2010related cytopenias. Venetoclax, a selective BCL\u20102 inhibitor, in combination with azacitidine, a hypomethylating agent, is currently being investigated in patients with previously untreated higher\u2010risk MDS. We present an integrated semi\u2010mechanistic pharmacokinetic\/pharmacodynamic (PK\/PD) model developed using preliminary clinical data from an ongoing Phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment\u2010na\u00efve patients with higher\u2010risk MDS. Longitudinal data from 57 patients were used to develop the model, which accounted for venetoclax PK and azacitidine treatment to describe time dynamics of bone marrow blasts, neutrophils, red blood cells, and platelets. The proliferation and maturation of progenitor cells in the bone marrow to peripheral cells is described via three parallel connected transit models including feedback terms. The model also accounted for bone marrow crowding and its impact on hematopoiesis. Model validation demonstrated adequate goodness\u2010of\u2010fit, visual and numerical predictive checks. Model predicted complete remission (CR) rates and marrow complete remission (mCR) rates closely matched observed rates in the clinical study, and simulated efficacy (recovery of blast count, CR, and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints aligned with expected outcomes from various dosing regimens. Importantly, the semi\u2010mechanistic model may aid understanding and discriminating between disease\u2010driven and drug\u2010induced cytopenias.<\/jats:p>","DOI":"10.1002\/psp4.13284","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T07:34:11Z","timestamp":1733816051000},"page":"448-459","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Semi\u2010mechanistic population <scp>PK<\/scp>\/<scp>PD<\/scp> model to aid clinical understanding of myelodysplastic syndromes following treatment with Venetoclax and Azacitidine"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0837-8676","authenticated-orcid":false,"given":"Neha","family":"Thakre","sequence":"first","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  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