Integration of Pharmacometrics & Systems Pharmacology (iPSP)

ISoP QSP Working Group on iPSP

The Integration of Pharmacometrics and Systems Pharmacology (iPSP) Working Group (WG) has the main goal of identifying, collecting & sharing useful information on best practices, examples, and approaches for integrating Systems Pharmacology & Pharmacometrics. The WG has good representation across industry, academia and the US FDA, with expertise spanning development and application of mechanistic and empirical models across the development/lifecycle of drugs/targets/biomarkers. The current and former members in this WG are listed in the table below.

The WG partakes monthly update calls involving all WG members to identify opportunities and implement them to drive the agenda forward. Over these last couple of years, the WG has successfully accomplished several tasks including developing several consensus proposals for scientific sessions in different conferences. Some of these are as follows:

• A session in PSWC 2017 titled, “Systems pharmacology – innovative approaches to drug safety” - Chairs: Mirjam N. Trame (University of Florida), Masanobu Sato (PMDA, Japan)

• Session proposals for ASCPT 2017, ACOP 2017 and ASCPT 2018

• ISOP Study Group Webinar Series in 2017 titled, “Bridging and tackling the gap between Empirical and Systems Pharmacology Models: Where do we stand?” (Youtube links embedded below)

The semantics and terminology of Quantitative and Systems Pharmacology and Pharmacometrics to help enable bridging (Piet van der Graaf)

Understanding, incorporating, characterizing variability and uncertainty in Quantitative Systems Pharmacology models: Case studies and experiences from Drug Development (Richard Allen)

Fix vs Fit – The eternal debate (Matt Riggs)

Systems pharmacology models for understanding drug safety signals (Melissa Hallow)

Good Practices in MID3 – PM & QSP approaches informing decisions (Sandra Visser)

MatVPC: A User-Friendly MATLAB-Based Tool for the Simulation and Evaluation of Systems Pharmacology Models (Konstantinos Biliouris)

PK-Sim/Mobi – Open Systems Pharmacology Suite (Jan Schlender)

· Publication in CPT:PSP in 2018 titled, “Perspective on the State of Pharmacometrics and Systems Pharmacology Integration”

· A session in ACoP 2018 titled, “A Perspective on integrating Pharmacometrics and Quantitative Systems Pharmacology characteristics using examples”

o Chairs: Mirjam N. Trame (University of Florida), Teun Post (LAP&P)

· A dedicated symposium in Aug 2019 on iPSP in collaboration with New England chapter of ISoP (ISoP-NE) in Boston, MA (agenda and slides at: https://sites.google.com/site/isopne/ipsp-august26-2019)

· Two session proposals for ACoP 2019 (accepted) titled, “Integrated Pharmacometrics and Systems Pharmacology (iPSP) Modeling Without Borders: Opportunities and Challenges for Re-purposing iPSP Models”¹ and “Curing Diseases Through Genetic Manipulation: Advancements and Potential of Gene and Viral Therapy and Their Optimization with Model-Based Analysis”²

o ¹Chairs: Anu Shilpa Krishnatry (GSK), Dan Kirouac (Applied BioMath)

o ²Chairs: Abhishek Gulati (Astellas), Weirong Wang (Janssen)

Boston Symposium (Aug 2019) Highlights

· Event organized by ISoP New England in collaboration with iPSP WG in Cambridge, MA

o ISoP NE: Chris Penland (Chair), Andy Zhu (Chair-Elect), Hong Lu (Communications)

o iPSP WG: Dhananjay Marathe, Abhishek Gulati (Co-Chairs)

o Conference space sponsored by Metrum

o ~50 attendees from industry/academia

· Key Themes:

o Open source and open model informed drug development: the dividends of, and the efficiency and robust scientific learning enabled by model adaptation and reuse

o Model identification and advanced modeling & simulation methods for iPSP class models

o Model Verification, Validation, and Uncertainty Quantification – adopting/adapting practices from physics-based modeling and simulation of medical devices

o Regulatory perspective on the use of iPSP-class models in decision making

o Case studies in bone preservation, cardiorenal/metabolic disease, immunology, and hematology

Conference Abstract Selected to Best Represent the WG Area of Interest

ACoP9: Title: Exenatide effects on gastric emptying and oral glucose appearance in plasma: A quantitative assessment using an integrative systems pharmacology model

Authors: Veronika Voronova¹, Kirill Zhudenkov¹, Robert C. Penland^2a, David W. Boulton^2b, Gabriel Helmlinger^2a, Kirill Peskov¹

Affiliations: ¹M&S Decisions, Moscow, Russia; ²Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech unit, AstraZeneca; ^2aBoston, USA; ^2bGaithersburg, USA.

ACoP10: Title: Combined application of Quantitative Systems Pharmacology (QSP) and PK-PD modeling to guide dose selection for a Phase 3 study of anti-TFPI therapy in patients with hemophilia

Authors: Satyaprakash Nayak¹, Chay Ngee Lim¹, Joan Korth-Bradley², Pinky Dua³, Tong Zhu¹ and Lutz O. Harnisch³

Affiliations: ¹Pfizer Inc, Cambridge, MA, USA; ²Pfizer Inc, Collegeville, PA, ³Pfizer Ltd., UK.

Future Goals:

· Recruitment for membership positions that are open in the WG (especially from organizations which are not already represented in the WG) – please reach out to Abhishek (abhishek.gulati@astellas.com) or Dhananjay (Dhananjay.Marathe@merck.com)

· Writing a summary article on the two ACoP 2019 sessions that originated from WG

· Currently working on completing outline for invited book (John Wiley and Sons) on “Integration of Quantitative and Systems Pharmacology Approaches”. Co-editors: Cynthia J Musante, Matthew Riggs, Mirjam N. Trame

· Explore possible hosting of local iPSP symposium in Chicago around ASCO timing (May-Jun 2020)

· Explore possible hosting of local iPSP symposium in NY/NJ/PA around Aug-Sep 2020

· Brainstorm and come up with session proposals for the upcoming 2020-2021 conferences (looking for cross-WG collaboration opportunities for possible sessions)