# Optimizing GVHD Prevention with Systems Pharmacology Models

> **NIH NIH U01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $600,003

## Abstract

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...

## Key facts

- **NIH application ID:** 9938520
- **Project number:** 5U01CA239373-02
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** DONALD E MAGER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $600,003
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938520

## Citation

> US National Institutes of Health, RePORTER application 9938520, Optimizing GVHD Prevention with Systems Pharmacology Models (5U01CA239373-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9938520. Licensed CC0.

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