Towards Quantitative Systems Pharmacology Models of Chemotherapy‐Induced Neutropenia

Craig, Morgan

doi:10.1002/psp4.12191

Cited by 36 publications

(47 citation statements)

References 92 publications

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“…Decrease in neutrophil count is managed by the dose reduction and delays that decrease the dose intensity, whereas maintaining the dose is important for favorable response to treatment. Furthermore, patients with neutropenic events are more prone to subsequent infections [ 13 – 16 ]. Another frequent and serious myelotoxic symptom in breast cancer chemotherapy is anemia.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

et al. 2018

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The differences in patients’ response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy.In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1).The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life.

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Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

et al. 2018

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“…Many compounds are known to be cytotoxic to hematopoietic cells, yet, cytopenias measured in the blood do not reflect the full extent of damage to the hematopoietic system(17). Understanding of mechanisms for myelosuppression would further inform first-in-human trials and help anticipate possible adverse-event mitigating strategies such as appropriate cytokine therapy by increasing evidence-based practices (3, 11). For instance, cytokine therapy is already employed for patients receiving anti-cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Drug-induced myelosuppression is one of the most severe adverse events (AEs) associated with anti-cancer therapies(1). Myelosupression increases patient fatigue and hinders their daily routines(2, 3), and increases patient risk for infection (4). Understanding patient propensity for AEs is required for clinical optimization of both drug selection and dose schedules.…”

Section: Introductionmentioning

confidence: 99%

Anin vitroquantitative systems pharmacology approach for deconvolving mechanisms of drug-induced, multilineage cytopenias

Wilson

Lü

Corr

et al. 2019

Preprint

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13Myelosuppression is one of the most common and severe adverse events associated with anti-14 cancer therapies and can be a source of drug attrition. Current mathematical modeling methods 15 for assessing cytopenia risk rely on indirect measurements of drug effects and primarily focus 16 on single lineage responses to drugs. However, anti-cancer therapies have diverse mechanisms 17 with varying degrees of effect across hematopoietic lineages. To improve predictive 18 understanding of drug-induced myelosuppression, we developed a quantitative systems 19 pharmacology (QSP) model of hematopoiesis in vitro for quantifying the effects of anti-cancer 20 agents on multiple hematopoietic cell lineages. We calibrated the system parameters of the 21 model to cell kinetics data without treatment and then validated the model by showing that the 22 inferred mechanisms of anti-proliferation and/or cell-killing are consistent with the published 23 mechanisms for three classes of drugs with different mechanisms of action. Using a set of 24 compounds as a sample set, we then analyzed novel compounds to predict their mechanisms 25 and magnitude of myelosuppression. Further, these quantitative mechanisms are valuable for 26 the development of translational in vivo models to predict clinical cytopenia effects. 27 28 Author Summary 29 Reduced bone marrow activity and levels of mature blood cells is an undesirable side effect of 30 many anti-cancer therapies. Selecting promising lead compounds for further development 39 40

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“…Model predictions generated scaling our mathematical model (Eqs. [1][2][3][4][5][6][7][8][9] to reflect the differences between rat and human haematopoiesis physiology (e.g., population size, maturation time, etc. ), but using the drug-effect parameters estimated in rats did not reflect accurately either clinical neutropenia or thrombocytopenia (Figure 4).…”

Section: Clinical Predictionsmentioning

confidence: 99%

Quantifying Drug‐Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model

Fornari

O’Connor

et al. 2019

CPT Pharmacom & Syst Pharma

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Haematological toxicity associated with cancer therapeutics is monitored by changes in blood cell count, and their primary effect is on proliferative progenitors in the bone marrow. Using observations in rat bone marrow and blood, we characterize a mathematical model that comprises cell proliferation and differentiation of the full haematopoietic phylogeny, with interacting feedback loops between lineages in homeostasis as well as following carboplatin exposure. We accurately predicted the temporal dynamics of several mature cell types related to carboplatin‐induced bone marrow toxicity and identified novel insights into haematopoiesis. Our model confirms a significant degree of plasticity within bone marrow cells, with the number and type of both early progenitors and circulating cells affecting cell balance, via feedback mechanisms, through fate decisions of the multipotent progenitors. We also demonstrated cross‐species translation of our predictions to patients, applying the same core model structure and considering differences in drug‐dependent and physiology‐dependent parameters.

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Towards Quantitative Systems Pharmacology Models of Chemotherapy‐Induced Neutropenia

Cited by 36 publications

References 92 publications

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

Anin vitroquantitative systems pharmacology approach for deconvolving mechanisms of drug-induced, multilineage cytopenias

Quantifying Drug‐Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model

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