ArticleCPT: pharmacometrics & systems pharmacology2025
Semi-mechanistic population PK/PD model to aid clinical understanding of myelodysplastic syndromes following treatment with Venetoclax and Azacitidine.
Article in CPT: pharmacometrics & systems pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Application of Population-Based Meta-Heuristic Algorithms for Robust Initialization in Mechanistic Pharmacometric Modeling.CPT: pharmacometrics & systems pharmacology · 2026Article
- Semi-mechanistic population PK/PD model to aid clinical understanding of myelodysplastic syndromes following treatment with Venetoclax and Azacitidine.CPT: pharmacometrics & systems pharmacology · 2025Article
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6 authors.
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Abstract
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-induced and treatment-related cytopenias. Venetoclax, a selective BCL-2 inhibitor, in combination with azacitidine, a hypomethylating agent, is currently being investigated in patients with previously untreated higher-risk MDS. We present an integrated semi-mechanistic 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-naïve patients with higher-risk 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-of-fit, 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-mechanistic model may aid understanding and discriminating between disease-driven and drug-induced cytopenias.
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