Malek, Kamel and Weber, Hans-Jochen (2026) Population PK/PD modelling for evaluation of intertwining effects of drug and disease on thrombocytopenia in acute leukaemias. CPT: pharmacometrics & systems pharmacology., 15. ISSN 2163-8306

Abstract

In haematological malignancies, thrombocytopenia is frequently observed at the time of diagnosis as a feature of the disease. Anti-leukaemic therapies are known to impact haematopoiesis and can worsen pre-existing thrombocytopenia. As a result, severe thrombocytopenia is commonly selected as a qualifying dose-limiting toxicity in early clinical trials. However, given the concurrent myelosuppressive effects of the drug and the underlying leukaemia, it can be difficult to differentiate whether the dose of the investigational treatment should be decreased or omitted to manage the observed thrombocytopenia or, on the contrary, increased in pursuit of higher efficacy to combat the disease. In this work, we evaluated the use of population PK/PD modelling as a valuable approach in such challenging situation, by characterising the dynamic relationship between drug exposure and blood counts, considering the underlying condition and drug effect. Clinical data from siremadlin, an investigational treatment for acute myeloid leukaemia (AML), was used in this analysis. Plasma concentrations of siremadlin and platelet counts in patients with haematological malignancies and solid tumours were used in model development to enable the differentiation of drug effect from disease effect on haematopoiesis. Subsequently, the potential utility of model averaged prediction to predict drug effect in patients following an allogeneic haemopoietic stem cell transplantation, with partially compromised bone marrow function, was also evaluated. The proposed modelling approach provides a feasible methodology that can be used represent recovering patients with different degrees of haematological malignancies and can be broadly applicable in similar clinical settings to support early decisions in drug development.

Item Type:	Article
Date Deposited:	24 Mar 2026 00:45
Last Modified:	24 Mar 2026 00:45
URI:	https://oak.novartis.com/id/eprint/57794