Abstract
Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.
Highlights
Neutrophils are a major class of white blood cells [1]
We develop a Quantitative systems pharmacology (QSP) model to represent avadomideinduced neutropenia. This is the first model developed for neutropenia caused by block in neutrophil maturation
The model consists in a proliferation pool, with proliferation rate kprol; a sequence of transit stages (transit 1, 2, 3, representing progressive maturation according to in vitro studies [39, 40]), with rate constants ktr1, ktr2, ktr3, ktr4; a bone marrow reservoir pool of mature neutrophils and final release, with kout rate constant, to peripheral blood
Summary
Neutrophils are a major class of white blood cells [1]. Neutrophils mature in the bone marrow, move to and reside in peripheral blood circulation, and migrate to inflamed tissue sites when necessary [2]. Neutrophils can degranulate, phagocyte microbes, or release cytokines to amplify inflammatory response [3]. The blood count of neutrophils (absolute neutrophil count or ANC) is a clinical metric for individual capability to fight infections. The work was conducted at Bristol Myers Squibb, Center for Innovation and Translational Research Europe (CITRE), Seville, Spain. Bristol Myers Squibb, Center for Innovation and Translational Research Europe (CITRE), Seville, Spain
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