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Optimizing GVHD Prevention with Systems Pharmacology Models

利用系统药理学模型优化 GVHD 预防

基本信息

批准号：
9757625
负责人：
Jeannine S McCune
金额：
$ 61.95万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757625
关键词：
Acute Graft Versus Host Disease Age Allogenic Area Cells Characteristics Cities Clinical Data Complex Computer Simulation Cyclophosphamide Data Disease Disease Pathway Disease Progression Dose Drug Kinetics Engraftment Enrollment Enzymes Equilibrium FOXP3 gene Goals Graft-Versus-Tumor Induction Human Hybrids IL2RA gene Immune response Immunosuppressive Agents In Vitro Individual Inosine Monophosphate Knowledge Link Malignant Neoplasms Metabolic Metabolic Pathway Modeling Mycophenolic Acid National Cancer Institute Nature Oxidoreductase Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Physiological Plasma Population Process Prodrugs Prospective cohort Publishing Regimen Regulatory T-Lymphocyte Retrospective cohort Sampling Schedule Severity of illness System T cell response T-Lymphocyte T-Lymphocyte Subsets Tacrolimus Testing Time Translations Transplant Recipients Weight base biological systems cohort cytotoxic disorder control disorder prevention experience experimental study graft vs host disease hematopoietic cell transplantation high risk immunoreaction improved mathematical model model building mortality mycophenolate mofetil novel pharmacodynamic model pharmacokinetic model pharmacokinetics and pharmacodynamics physiologically based pharmacokinetics population based post-transplant pre-clinical prospective standard of care study population success

项目摘要

PROJECT SUMMARY Quantitative systems pharmacology (QSP) is a rapidly expanding area that integrates available in vitro, preclinical, and clinical data representing existing knowledge to achieve a reverse translation. Reverse translation uses real-time human clinical data to directly inform new discoveries, of existing therapies and attributes of disease progression. Here, we seek to be the first to build a QSP model to, a priori, predict interpatient pharmacokinetics and pharmacodynamics using population priors (population pharmacokinetic or popPK modeling) and physiologic predictions (using physiologically based pharmacokinetic or PBPK modeling) combined with pharmacodynamic models based on in vitro and preclinical data. We will apply this novel hybrid popPK-PBPK-PD QSP model to allogeneic hematopoietic cell transplant (HCT) because its success requires a delicate balance as the grafting of cells from one individual (donor) to another (host, the HCT recipient). Guided by our preliminary data, our working hypothesis is that QSP modeling can minimize interindividual variability of these immunosuppressants, while also optimizing the novel graft versus host disease (GVHD) regimen of post- transplant cyclophosphamide (PTCy). Aim 1 seeks to identify the optimal PTCy dose using popPK and PBPK models. Our preclinical data shows that PTCy has a narrow dose window, with intermediate doses having the lowest GVHD rates. To achieve the optimal PTCy dose in each patient, we seek to develop a validate a popPK- PBPK model building upon our unique expertise in quantitating 4-hydroxycyclophosphamide (4HCY), the primary precursor to the cytotoxic metabolite of CY and personalizing CY using popPK-guided dosing. This hybrid popPK-PBPK CY model will be developed using our retrospective and prospective (n=150) cohort. The prospective cohort will be enrolled at National Cancer Institute (NCI) and City of Hope (COH). The NCI cohort will determine if the PTCy dose and schedule can be reduced (by 75%) without compromising GVHD rates; the COH cohort will use the traditional PTCy dosing. In Aim 2, we will characterize the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA), the active metabolite of MMF, with its target enzyme inosine monophosphate dehydrogenase (IMPDH). Like CY, MPA has substantive pharmacokinetic variability but different metabolic and transport pathways so separate pharmacokinetic models are needed. We seek to create a popPK-PBPK-PD model to identify the optimal plasma exposure of MPA and IMPDH activity. In Aim 3, we will create a quantitative systems pharmacology (QSP) model of T-cell response and acute GVHD. Our preclinical data show that acute GVHD prevention with PTCy is associated with reduction of CD4+CD25-Foxp3- conventional T-cell (Tcon) proliferation at day +7 followed by the preferential expansion of CD4+CD25+Foxp3+ regulatory T cells (Tregs) at day +21. Building upon fully-integrated immune response model (FIRM), we seek integrate in vitro, preclinical, and clinical data to build a QSP model.

项目总结