Systems Pharmacology

A Quantitative Modeling and Simulation Framework to Support Candidate and Dose Selection of Anti-SARS-CoV-2 Monoclonal Antibodies to Advance Bamlanivimab Into a First-in-Human Clinical Trial

Neutralizing monoclonal antibodies (mAb) have emerged as promising therapeutics for COVID-19, with research efforts accelerated through open-access in silico models. Innovative approaches, including a physiologically-based pharmacokinetic (PBPK) model and a longitudinal SARS-CoV-2 viral dynamic model, facilitated the selection of optimal mAb candidate and therapeutic dose. By utilizing these models, the first-in-human trial of bamlanivimab (NCT04411628) initiated with a conservative dose of 700 mg, aiming to achieve maximum therapeutic effect while ensuring safety and tolerability.

Quantitative systems pharmacology modeling of loncastuximab tesirine combined with mosunetuzumab and glofitamab helps guide dosing for patients with DLBCL

Presented at AACR Annual Meeting 2024. QSP model simulations were used to predict anti-tumor efficacy and guide dosing of the antibody-drug conjugate Loncastuximab tesirine combined with T cell-dependent bispecific antibodies, Mosunetuzumab or Glofitamab for the treatment of B-cell malignancies.

Making drugs from T cells: The quantitative pharmacology of engineered T cell therapeutics

Engineered T cells, particularly CAR T cells, have revolutionized hematological cancer treatment. However, their complexity poses challenges. This research explores how mathematical models, utilizing clinical data, can elucidate relationships between product characteristics, patient physiology, and clinical outcomes, thereby facilitating the development of next-generation cell therapies.

An Open Source Package Suite in Julia to Facilitate QSP Modeling and Simulation

Presented at ACoP14. Here, we introduce a pair of packages PMParameterized.jl which simplifies specification of parameters and initial conditions for Ordinary Differential Equation models, and PMSimulator.jl which enables complex dosing, inputs and events. Together these packages result in stateful, reproducible models and simulation for a quantitative systems pharmacology and pharmacometrics workflow in the Julia language.

Hierarchical Deep Compartment Modeling: A Workflow to Leverage Machine Learning for Hierarchical Pharmacometric Modeling

Oral presentation for ACoP14 Abstract Quality Award winner. The Hierarchical Deep Compartment Modeling (HDCM) framework introduced in this abstract was developed using open-source tools in the Julia Programming Language and integrated Bayesian inference to quantify the uncertainty around the model parameters. It provides a convenient, readily accessible HDCM framework to the pharmacometrics community interested in applying deep learning to hierarchical compartmental models.

In relapsed or refractory diffuse large B-cell lymphoma, CD19 expression by immunohistochemistry alone is not a predictor of response to loncastuximab tesirine

This study explores Lonca’s efficacy across varying CD19 expression levels, revealing its effectiveness in patients, regardless of low or undetectable CD19 levels by conventional methods. The study integrates quantitative systems pharmacology (QSP) modeling to predict treatment responses, indicating that CD19 expression alone may not predict Lonca’s effectiveness, however, response predictions are improved by considering CD19 surface density.

Deep QSP Modeling: Leveraging Machine Learning for QSP Model Development and Evaluation

Presented at ACoP14. DQSP framework successfully implemented a UDE that characterized the PK of remoxipride and its effect on PRL release from lactotrophs to plasma. The model also characterized the positive feedback effect of plasma PRL on lactotroph PRL stimulation using an ANN.

A multi-organ integrated QSP model for hematopoietic stem cell differentiation to predict the immune cell reconstitution in ex-vivo gene therapy

Presented at ACoP14. The differentiation of mammalian hematopoietic stem cells (HSCs) is complex and multiscale, providing an opportunity for mathematical modeling and simulation to aid in mechanistic understanding, and ultimately, to inform drug development efforts. Historically, HSC mathematical models were focused on the development of a subset of cells, but mathematical models encompassing the overall cellular system’s complexity are rarely available. Here, an integrated quantitative systems pharmacology (QSP) model that characterizes multi-organ HSC differentiation was developed by integrating literature models and adding novel features.

Exploring the Influence of Bispecific Antibody Mechanisms on In Vitro Dose Response: Insights from an Open-Science Quantitative Systems Pharmacology Model in Julia

Presented at ACoP14. Analysis of the QSP model found that the internalization rate of the target receptors may be an important, yet often underestimated, factor for understanding bsAb efficacy in vitro. Simulations of the model indicated that high rates of receptor turnover can increase model predictions of efficacy, particularly at higher antibody concentrations.

Hands-On Tutorial: Introduction to Immuno-Oncology (IO) Quantitative Systems Pharmacology (QSP) Modeling Using the Open Source Julia Programming Language

ACoP14 pre-meeting workshop. Highlights include exploring Julia as an open source alternative for QSP support of model-informed drug development, gaining insights into IO QSP modeling for antibody drug conjugate (ADCs) and bispecific mAb (bsAb) therapies to drive your own implementations of Project Optimus, and accessing open source Julia versions of two pivotal IO models and parameterizations.

Quantitative Systems Pharmacology in Model-Informed Drug Development

When tailored for specific questions, QSP models enhance our grasp of clinical observations, guiding research with informed decisions, especially when they incorporate mechanistic insights. These models facilitate the integration of theory and data to test our understanding and explore the root causes of events. By offering quantifiable insights into the interactions within physiology, disease, and pharmacology, QSP models steer further research, impacting study design and biomarker selection. The presentation will encompass case studies on monoclonal antibody (mAb) development in bone health (osteoporosis), infectious disease (SARS-CoV-2), and oncology (relapsed/refractory diffuse large B-cell lymphoma).

A Clinical Quantitative Systems Pharmacology Framework Describing Loncastuximab Tesirine Distribution and to Explore Patient Outcomes From the LOTIS-2 Clinical Trial in Patients With B-cell Lymphomas

A novel QSP framework integrating PBPK modeling with tumor dynamics was developed using literature and in-house data. By employing a virtual population reflecting patients treated with Lonca, it is possible to evaluate indication, clinical population selection, influence of clinical study covariates, disease phenotypes, and CD19 expression levels on clinical responses

Towards the development of a platform PBPK-QSP model in the Julia programming language for evaluating potential toxicities caused by antibody-drug-conjugate therapies

Antibody-drug conjugates (ADCs) are promising anti-cancer drugs but often cause toxicities in clinical use. This poster presents a new model that predicts toxicities of ADCs, including liver and lung effects for drugs like T-DM1 and T-Dxd, and high hepatotoxicity in CM.

Open-Science Immuno-Oncology QSP Modeling Using Open-Source Julia Solvers

As Julia usage continues to grow within regulated biomedical environments, it is vital to ensure analyses are traceable and reproducible. Conducting analyses in an open-science manner is also critical to expand the adoption of Julia and to facilitate the infrastructure growth of Julia as an accessible ecosystem. A step-by-step model-building example of a classic monoclonal antibody-drug conjugate PBPK/tumor dynamics system illustrates how to develop such a reproducible open-science framework.

A physiologically-based pharmacokinetic modeling approach to support candidate and first in human dose selection for bamlanivimab

Tim Knab, Ahmed Elmokadem, Emmanuel Chigutsa, Eric Jordie, Matthew Riggs, Patricia Brown-Augsburger, Christopher Wiethoff, Ajay Nirula, Jenny Y Chien, Lisa O’Brien.  Poster presented at Population Approach Group Europe Annual Meeting; 2-3 and 6-7 September 2021.  Poster I-64.

Dosing regimen optimisation for oseltamivir in immunocompromised paediatric patients with influenza: Extrapolation of efficacy

Jordie EB, Gibiansky L, Knab T, Lemenuel-Diot A, Ravva P, Zwanziger E, Jolivet S, Bhardwaj R, Hernández-Sánchez J, Nasmyth-Miller C, Sturm S. Br J Clin Pharmacol. 2021;1-13. doi:10.1111/bcp.15059

Brexpiprazole Pharmacokinetics in CYP2D6 Poor Metabolizers: Using Physiologically Based Pharmacokinetic Modeling to Optimize Time to Effective Concentrations

Elmokadem A, Bruno CD, Housand C, Jordie EB, Chow CR, Lesko LJ, Greenblatt DJ.  J Exp Pharmacol20211– 10. doi:10.1002/jcph.1946

CPT: Pharmacometrics & Systems Pharmacology – Inception, Maturation, and Future Vision.

Rowland Yeo K, Hennig S, Krishnaswami S, Strydom N, Ayyar VS, French J, Sinha V, Sobie E, Zhao P, Friberg LE, Mentré F.
CPT Pharmacometrics Syst Pharmacol. 2021 Jul;10(7):649-657. doi: 10.1002/psp4.12680.

Development and evaluation of a predictive model of hyperphosphatemia induced by inhibition of FGFR by extending an existing multiscale systems pharmacology

Matthew M. Riggs, Howard A. Ball, Kanji Komatsu, Akihiro Yamada.  Poster presented at 2020 American Conference on Pharmacometrics (ACoP11) virtual meeting. 10 November 2020.

Model code and supporting material is available here.

A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

Eric Burroughs Jordie, Ahmed Elmokadem, Mohammad Azab, and Aram Oganesian

Presented by Eric Jordie at American Conference on Pharmacometrics 2019.

Bridging Knowledge Gaps in PBPK through Open Science

Presented by Marc Gastonguay, Ph.D at Development of Best Practices in Physiologically Based Pharmacokinetic Modeling to Support Clinical Pharmacology Regulatory Decision -Making Sponsored by the Office of Clinical Pharmacology OTS, CDER, U.S. Food and Drug Administration (FDA) on 18 November 2019. Event information here. Slides are here

Transparent, Open and Reproducible PBPK and QSP Modeling and Simulation Using an R-Based Framework

Presented by Ahmed Elmokadem, Ph.D at the 9th Annual CTSI Disease and Therapeutic Response Modeling and Simulation Symposium at Indiana University School of Medicine on November 12, 2019. Event details can be found here.

Open-Source and Open-Science to Progress the Integration of Pharmacometrics and Systems Pharmacology

Riggs, Matthew. Presentation at ISoPNE iPSP event. Cambridge, MA. 26 Aug 2019.

Development of an open-source physiologically-based pharmacokinetic model to predict maternal-fetal exposures of CYP450-metabolized drugs

Gastonguay MS, Russell S, Freling R, Riggs M, Kay K, Utsey K, Elmokadem A.

Poster presented at 2019 American Society for Clinical Pharmacology & Therapeutics (ASCPT). Washington DC. 14 March 2019.

Poster presented at ISoP Regional QSP Day 2019. Princeton, NJ. 16 July 2019.

Systems Pharmacology: A day in the life

Riggs MM. Slides presented at AAPS Forum to Connect Predictive Modelers in Boston, MA. 6 May 2019.

When learn/confirm leads to expand/understand: The expanding role of quantitative systems pharmacology in the betterment of therapeutics development

Riggs MM. Clin Pharmacol Ther. 98:394. 18 December 2018. doi: 10.1002/cpt.1287

A perspective on the state of pharmacometrics and systems pharmacology integration

Trame MN, Riggs MM, Biliouris K, Marathe D, Mettetal J, Post TM, Rizk ML, Visser SAG, Musante CJ.  CPT Pharmacometrics Syst Pharmacol. doi:10.1002/psp4.12313. 21 August 2018.

Systems pharmacology model development to provide physiologically based interpretation and drug development decision support in osteoporosis and other bone mineral-related diseases

Riggs, M.  Presented at Pharmacology 2016, annual meeting of the British Pharmacological Society, London, December 2016.

Comparing the performance of four open-source methods for multiple parameter estimation in a systems pharmacology model

Eudy RJ, Riggs MM, Baron K.  Presented at the Sanofi–MSISB Mount Sinai Systems Pharmacology Symposium, June 2016.

Simulation from ODE-based population PK/PD and systems pharmacology models in R with mrgsolve

Baron KT and Gastonguay MR.  Presented at the 6th American Conference on Pharmacometrics (ACoP), Arlington, VA; October 2015.

Linking a mechanistic model of bone mineral density to a time-to-event model of fracture

Eudy RF, Gillespie WR, Riggs MM, Gastonguay MR.  Presented at the 6th American Conference on Pharmacometrics (ACoP), Arlington, VA; October 2015.

Modeling & simulation: Filling the knowledge gap in rare diseases. Return on Investment on the Utilization of Systems Pharmacology and pharmacometrics in drug development for rare diseases: challenges and opportunities

Gastonguay MR and Godfrey CJ.  American College of Clinical Pharmacology (ACCP) Workshop, September 26, 2015.

Connecting the dots: Linking osteocyte activity and therapeutic modulation of sclerostin by extending a multiscale systems model

Eudy RJ, Gastonguay MR, Baron KT, and Riggs MM.  CPT: Pharmacometrics & Systems Pharmacology. 2015;4(9):527-536. doi:10.1002/psp4.12013.

Sclerostin-mediated osteocyte control in bone remodeling: Extension of a multiscale systems model to consider new therapies for osteoporosis

Eudy RJ, Gastonguay MR, Baron KT, Riggs MM.  Presented at the Annual Meeting of the Population Group in Europe (PAGE), Hersonnisos, Greece; June 2015.

FDA advisory meeting clinical pharmacology review utilizes a quantitative systems pharmacology (QSP) model: A watershed moment?

Peterson MC and Riggs MM.  CPT: Pharmacometrics & Systems Pharmacology, 2015 Mar; 4(3).

Extensions of a multiscale systems pharmacology model of bone mineral balance and its regulation of bone health

Riggs MM. Presented at Sunrise Session: Integration of Systems Modeling in Clinical Development: Successes, Challenges, and Future Outlook at the American American Society for Clinical Pharmacology and Therapeutics Annual Meeting, 2013.

Systems pharmacology model development to provide physiologically-based interpretation and drug development decision support in osteoporosis and other bone-related diseases

Riggs M.  Presented at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, 2013.

An evaluation of calcilytic effects on parathyroid hormone and bone mineral density response using a physiologically-based, multiscale systems pharmacology model

Kyle T. Baron, Matthew M. Riggs, Ryoko Sawamura, Takako Shimizu, Fumihiko Okada, Jin Zhou, Takahiro Shibayama, Mendel Jansen. Presented at the American Society of Bone and Mineral Research (ASBMR), October, 2013.

Predicting nonlinear changes in bone mineral density over time using a multiscale systems pharmacology model

Peterson MC and Riggs MM. CPT Pharmacometrics Syst Pharmacol. 2012 Nov; 1(11): e14. Published online 2012 Nov 14. doi: 10.1038/psp.2012.15

Integrated pharmacometrics and systems pharmacology model-based analyses to guide GnRH receptor modulator development for management of endometriosis

Riggs MM, Bennetts M, van der Graaf PH, and Martin SW.  CPT Pharmacometrics Syst Pharmacol. 2012 Oct; 1(10): e11. Published online 2012 Oct 17. doi: 10.1038/psp.2012.10

Qualification of a physiologically-based model for predicted bone marker and bone mineral density changes associated with denosumab treatment

Riggs MM, Baron KT, Plan EL, Gastonguay MR. Presented at American Society of Bone Mineral Research (ASBMR) Annual Meeting, Minneapolis, MN; October 14, 2012 (Abstract SU0363).

Bayesian joint modeling of bone mineral density and repeated time-to-fracture event for multiscale bone systems model extension

Plan EL, Baron KT, Gastonguay MR, French JL, Gillespie WR, and Riggs MM. Presented at the 21st Annual Meeting of the Population Approach Group Europe (PAGE), Venice, Italy, 2012, Abstract 2592.

Systematic extension of a physiologic model of bone and calcium homeostasis

Riggs MM. . Presented at the AAPS Biotechnology Conference, San Diego, CA; May 22, 2012.

Multiscale physiology-based modeling of mineral bone disorder in patients with impaired kidney function

Riggs MM, Peterson MC, Gastonguay MR. The Journal of Clinical Pharmacology. 52(1 Suppl):45S-53S. January 2012. doi:10.1177/0091270011412967


Applying a multiscale physiologic system model to evaluate bone-related disease and therapeutic responses

Riggs MM. Presented at First Indiana Clinical and Translational Sciences Institute (CTSI) Symposium on Disease and Therapeutic Response Modeling. Indiana University – Purdue University Indianapolis; Indianapolis, IN; 13 November 2011.