Methodology, Tools, and Computation

Population pharmacokinetic modeling of vedolizumab for graft-versus-host disease prophylaxis in adults with Allogeneic Hematopoietic Stem Cell Transplant.

This study characterizes the population pharmacokinetics (PK) of vedolizumab in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for graft-versus-host disease (GvHD) prophylaxis. The analysis identified body weight and albumin levels as significant predictors of vedolizumab clearance, though the covariates studied had no clinically meaningful effect on its overall PK. The findings offer important insights into dosing strategies for vedolizumab in this patient population.

A Modern Curriculum for Training Scientists in Model-Informed Drug Development: Progress Report on FDA Grant to Train Regulatory Scientists

The paper details a collaborative initiative funded by the FDA, where the Critical Path Institute and partners created didactic e-learning materials on model-informed drug development (MIDD) for non-modeling audiences. The curriculum, enriched with case studies from multinational pharmaceutical companies, includes 13 hours of training videos and is currently being beta-tested by FDA reviewers. Future plans involve expanding the content, offering 1:1 mentorship sessions, and providing broader access to the learning management system to support global stakeholders and the evolving MIDD community.

Explore MeRGE: the Metrum Research Group Ecosystem

Presented at PAGE 2024 – Hands-on Workshop. MeRGE is a suite of freely-available, open-source tools for scalable, reproducible pharmacometric workflows. MeRGE consists of individual but interconnected R packages that support scalability and reproducibility during: project setup, data assembly, data exploration, model development, execution, and evaluation, simulation, and reporting.

Population pharmacokinetic-pharmacodynamic (popPKPD) model of the impact of iclepertin on hemoglobin levels.

Presented at PAGE 2024. This model, developed by Boehringer Ingelheim in collaboration with Metrum Research Group, provides insights into potential anemia risks and informs monitoring strategies for patients with cognitive impairment associated with schizophrenia.

Formalizing “Similarity” in Pediatric Extrapolation Plans using Causal Selection Diagrams

Presented at the 37th New England Statistics Symposium (NESS).Dr. Jim Rogers from MetrumRG as he illustrates the use of causal inference frameworks for evaluating pediatric extrapolation plans.

Covariate modeling in pharmacometrics: General points for consideration

Covariate analysis is typically performed, and results are reported, based on the purpose of the analysis and the anticipated audience. Failure to use a standard for reporting parameters has made it difficult to find common features of models and use covariate analysis in a consistent way in order to discover new knowledge. This article aims to provide a useful basis for analysts to choose the most appropriate approach for their specific sets of circumstances.

An Introduction to R Programming Language

Presented by Dr. Sam Callisto and Michael Heathman at the CTSI Disease and Therapeutic Response Modeling Symposium, February 2024.
View presentation recording.

A pharmacokinetic and enzyme turnover model predicts major roles for cyp2b6 genotypes on the magnitude of efavirez autoinduction of metabolism and clearance in healthy volunteers.

Presented at ASCPT Annual Meeting 2024. A population PK and turnover models were developed and show that the extent of efavirenz autoinduction and clearance is dependent on CYP2B6 genotype.

Consistency between ML and Classical Approaches for Covariate Identification

Presented at ASCPT Annual Meeting 2024. Discover the synergy between Machine Learning and classical approaches in covariate identification. Our scientist, Matthew Wiens, explored this vital topic at the pre-conference session ‘Empowering Clinical Pharmacologists and Translational Scientists Using Artificial Intelligence: Unlocking Potential with Cutting-Edge Use Cases.’

MIDD for dose confirmation in special populations: full covariate modeling meets intersection-union testing

Presented at the International Symposium on Biopharmaceutical Statistics, March 2024. From basic dose adjustments to more ambitious programs for personalized medicine, pharmacometrics has a long tradition of informing tailored treatment strategies. Many of the modeling strategies are well-precedented, but formal decision frameworks are needed to address the question: how much data is enough to support a decision?

Challenging the Norm: A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics

This research delves into the significance of transitioning from intravenous (i.v.) to subcutaneous (s.c.) administration of biologics in enhancing patient convenience and treatment outcomes. It emphasizes the role of model-informed drug development (MIDD) in facilitating this transition, providing insights into crucial clinical pharmacology and regulatory considerations. Key aspects highlighted include comprehensive pharmacokinetic evaluations, exposure-response profiling, comparability studies, and safety assessments, with MIDD strategies aiding in expediting the shift to s.c. dosing, thereby improving patient adherence and clinical efficacy.

gPKPDviz: A flexible R shiny tool for pharmacokinetic/pharmacodynamic simulations using mrgsolve

GPKPDviz is a Shiny application designed for real-time simulation, visualization, and assessment of PK/PD models. The app allows the generation of virtual populations, simulation of diverse dosing scenarios, and assessment of covariate and dosing regimen impacts on PK/PD endpoints. It supports loading actual population data from clinical trials and offers a streamlined workflow for efficient modeling.

Bayesian Semi-Parametric Approaches to Exposure-Response Modeling with Time-to-Event Outcomes

Introduction to exposure-response (E-R) concepts. Presented at the 79th Annual Deming Conference on Applied Statistics.

Bayesian estimation in NONMEM

In this tutorial, the principles of Bayesian model development, assessment and prior selection are outlined. An example pharmacokinetic model is used to demonstrate the implementation of Bayesian modeling using the nonlinear mixed-effects modeling software NONMEM.

Expanding Statistical Influence in Pharmacometrics: What it Means, Why it Matters, and How to Make it Work

Many biostatisticians in pharma and biotech  have relatively little awareness of, let alone influence over, the heavily statistical “pharmacometric” reasoning that goes into CTD Section 2.7.2 of an FDA regulatory submission, the “Summary of Clinical Pharmacology Studies”.  This talk focuses on the value of increasing statistical influence in pharmacometrics and the path to get there.

simpar: an R Package for Parameter Uncertainty Simulations in Pharmacometric Modeling

Presented at ACoP14. This project is dedicated to integrating parameter uncertainty into pharmacometric simulations, which plays a crucial role in making informed decisions in drug development. Initially, the metrumrg package in R was instrumental for simulating both fixed and random effect parameters. However, this package has since been deprecated. Consequently, the primary objective was to create a new R package named simpar. This new package aimed to retain the essential functionalities of metrumrg while expanding its capabilities. The overarching goal was to significantly enhance the support for incorporating parameter uncertainty into pharmacometric simulations, thereby aiding more comprehensive and accurate decision-making processes in this field.

UDE Know It If UDE Saw It: Leveraging Deep Machine Learning for QSP Model Development and Evaluation

Roller Coaster Talk presented at ACoP14. A workflow was introduced that integrates QSP modeling and machine learning in the form of UDEs. The workflow utilizes machine learning to learn missing parts in our knowledge of a QSP system while quantifying the uncertainty around the learned dynamics using Bayesian analysis.

Illustrating Integration and Interpretation of the Deep Compartment Model Approach using Keras and R in a Population PK Modeling Analysis

Presented at ACoP14. Deep compartment models (DCMs) are a proposed alternative to traditional nonlinear mixed effect (NLME) pharmacometrics approaches [1]. DCM uses neural networks to represent estimated pharmacokinetic parameters which can then be used in either closed-form or ordinary differential equation (ODE)-based representations of pharmacokinetic models

Dosing Recommendation Based on the Effects of Different Meal Types on Pexidartinib Pharmacokinetics in Healthy Subjects: Implementation of Model-informed Drug Development Strategy

A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development

Ana Ruiz-Garcia, Paul Baverel, Dean Bottino, Michael Dolton, Yan Feng, Ignacio González-García, Jaeyeon Kim, Seth Robey, Indrajeet Singh, David Turner, Shu-Pei Wu, Donghua Yin, Di Zhou, Hao Zhu, Peter Bonate. J Pharmacokinet Pharmacodyn. March, 4 2023

An Introduction to Bayesian Estimation in NONMEM

Tim Waterhouse. Presented at 12th Annual Indiana Clinical and Translational Sciences Institute (CTSI) Symposium on Disease and Therapeutic Response Modeling. February 23, 2023.

A Showcase of Open-Source Tools for Scalable, Reproducible Pharmacometrics Workflows

Sam Callisto, Tim Waterhouse. Presented at 12th Annual Indiana Clinical and Translational Sciences Institute (CTSI) Symposium on Disease and Therapeutic Response Modeling. February 23, 2023.

Variable or variate? A conundrum in pharmacometrics exposure–response models

Ana-Marija Grisic, Karthik Venkatakrishnan, Jonathan French, Akash Khandelwal. CPT Pharmacometrics Syst Pharmacol.  December, 20 2022. doi:10.1002/psp4.12905

A Population Pharmacokinetic-Pharmacodynamic Model Evaluating Efficacy of Nalbuphine Extended-Release in Patients with Prurigo Nodularis

Rena Eudy-Byrne, Matthew Riggs, Amale Hawi, Thomas Sciascia, Shashank Rohatagi. Br J Clin Pharmacol. 2023.  doi:10.1111/bcp.15663

Bayesian PBPK Modeling using R/Stan/Torsten and Julia/SciML/Turing.jl

Ahmed Elmokadem, Yi Zhang, Timothy Knab, William R. Gillespie. CPT Pharmacometrics Syst Pharmacol.  January, 20 2023. doi:10.1002/psp4.12926

Shrinkage in Population PK/PKPD Analysis

Sonoko Kawakatsu. Virtual presentation for Children’s Hospital of Philadelphia and Cincinnati’s Children’s Hospital. 13 December 2022.

Emerging use of real-world data to address data gaps in clinical pharmacology: Opportunities and challenges

Simon Dagenais, Marc Gastonguay, Abie Ekangaki. Hot topic presented at 2022 AAPS PharmSci360. 17 October 2022.

An Introduction to Causal Inference for Pharmacometricians

James Rogers, Hugo Maas, Alejandro Perez Pitarch. CPT Pharmacometrics Syst Pharmacol.  November, 16 2022. doi:10.1002/psp4.12894

Disease Trajectory of SLE Clinical Endpoints and Covariates Affecting Disease Severity and Probability of Response: Analysis of Pooled Patient-Level Placebo (Standard-of-Care) Data to Enable Model-Informed Drug Development

Kosalaram Goteti, Jonathan French, Ramon Garcia, Ying Li, Florence Casset-Semanaz, Aida Aydemir, Robert Townsend, Cristina Vazquez Mateo, Matthew Studham, Oliver Guenther, Amy Kao, Marc Gastonguay, Pascal Girard, Lisa Benincosa, Karthik Venkatakrishnan. CPT Pharmacometrics Syst Pharmacol.  November, 9 2022. doi:10.1002/psp4.12888

Application of Model-Based Meta-Analysis to Set Benchmarks for New Treatments of Systemic Lupus Erythematosus

Kosalaram Goteti, Ramon Garcia, William Gillespie, Jonathan French, Lena Klopp-Schulze, Ying Li, Cristina Vazquez Mateo, Sanjeev Roy, Oliver Guenther, Lisa Benincosa, Karthik Venkatakrishnan. Poster presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October – November 2 2022. Poster T-075

A showcase of open-source tools for scalable, reproducible PMx workflows

Kyle Baron, Sam Callisto, Seth Green, Matthew Riggs. A showcase of open-source tools for scalable, reproducible PMx workflows. Pre Meeting Workshop presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October 2022.

Bayesian PBPK Modeling using R/Stan/Torsten and Julia/SciML/Turing.jl

Ahmed Elmokadem, Yi Zhang, Tim Knab, Eric Jordie, William R. Gillespie. Poster presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October – November 2 2022. Poster W-074

Analysis Planning and Interpretation Using Causal Directed Acyclic Graphs: A Case Study in Oncology

James A. Rogers, Hugo Maas, Alejandro Peréz. Poster presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October – November 2 2022. Poster T-022

A Suite of Open-Source Tools to Guide Efficient Pharmacometric Analyses

Katherine Kay, Kyle Baron, Seth Green, Samuel Callisto, Curtis Johnston, Kyle Barrett, Devin Pastoor, Jim Rogers, Ana Ruiz-Garcia, Tim Waterhouse, Matthew Wiens, Matthew Riggs. Poster presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October – November 2 2022. Poster M-062

Using Graphical Models and Causal Thinking to Inform Pharmacometric Modeling

Jonathan French. Presented at Bayes 2022. 12 – 14 October 2022.

Using Quarto to showcase an ecosystem of open-source R packages for Pharmacometrics

Seth Green. Presented at R/Medicine 2022. 26 August 2022.

Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data

Jeffrey S. Barrett, Megan Cala Pane, Timothy Knab, William Roddy, Jack Beusmans, Eric Jordie, Kanwaljit Singh, Jonathan Michael Davis, Klaus Romero, Michael Padula, Bernard Thebaud, Mark Turner. Front. Pharmacol. 2022 October 12. doi: 10.3389/fphar.2022.988974

Flexible and efficient Bayesian pharmacometrics modeling using Stan and Torsten, Part I

Charles C. Margossian, Yi Zhang, William R. Gillespie. Flexible and efficient Bayesian pharmacometrics modeling using Stan and Torsten, Part I. CPT Pharmacometrics Syst Pharmacol. 2022 May 15. doi: 10.1002/psp4.12812. Epub ahead of print. PMID: 35570331.

Modeling Reaction Time Distributions Increases the Statistical Power of Cognition Testing

Seth C. Hopkins, Sean D. Wilson, Ajay Ogirala, Gabriel Stellman, Snezana M. Milanovic, Steven T. Szabo, James A. Rogers, Chris J. Edgar, Kenneth S. Koblan. Poster presented at 2021 American College of Neuropsychopharmacology. 5-8 December 2021.

I’m a Bayesian and I’m OK: Or How I Learned to Stop Worrying and Love Variability and Uncertainty

William R. Gillespie. The Lewis B. Sheiner Lecturer Award slides presented at International Society of Pharmacometrics. November 2021.

A Torsten case study: Evaluating the benefits of cross-chain communication during the warmup phase of Hamiltonian Monte Carlo (HMC) simulation

Yi Zhang and William R. Gillespie. Poster presented at 2021 American Conference on Pharmacometrics (ACoP12) virtual meeting. 8-12 November 2021. Poster PIIIB-028

Development and validation of open-source pharmacometrics software using an iterative software development life cycle methodology: the pmtables R package for submission-ready table generation

Kyle T. Baron, Devin Pastoor, Anna Nevison, Katherine Kay, Marc R. Gastonguay. Poster presented at Population Approach Group Europe Annual Meeting; 2-3 and 6-7 September 2021.  Poster III-02.

Torsten: Stan functions for pharmacometric applications – Improvements and new R interface workflow

Yi Zhang and William R. Gillespie.  Poster presented at Population Approach Group Europe Annual Meeting; 2-3 and 6-7 September 2021.  Poster I-61.

Decision making in drug development: An opportunity for model-based knowledge integration and scenario evaluation.

Seminar presented by Marc R. Gastonguay, Ph.D., at the FDA’s Model Informed Drug Development (MIDD) Education Series, April 26, 2021 (virtual).

Opportunities at the Intersection of Pharmacometrics and Health Economics for Insightful Drug Development Decision Making

Marc Gastonguay, Jing Liu, Jean Lachaine, Anna G. Kondic, and Daniel Polhamus.  Presented at the American Society for Clinical Pharmacology (ASCPT) annual meeting, March 15, 2021.

Theory, Empiricism, Certain Random Events, and a Vision for the Continued Growth of Pharmacometrics

Presentation by Marc Gastonguay for the ASCPT Sheiner-Beal Award during the American Society for Clinical Pharmacology (ASCPT) annual meeting, March 11, 2021.

Complex genetic dependencies among growth and neurological phenotypes in healthy children: Towards deciphering developmental mechanisms

Uechi L, Jalali M, Wilbur JD, French JL, Jumbe NL, Meaney MJ, Gluckman PD, Karnani N, Sakhanenko NA, Galas DJ; GUSTO study group. PLoS One. 2020 Dec 3;15(12):e0242684. doi: 10.1371/journal.pone.0242684.

Speed up population Bayesian inference by combining cross-chain warmup and within-chain parallelization

Yi Zhang, William R. Gillespie, Ben Bales, Aki Vehtari.  Poster presented at 2020 American Conference on Pharmacometrics (ACoP11) virtual meeting. 11 November 2020.

 

Improving strategic decision-making with early prediction of survival outcomes in oncology clinical trials

Presentation by Jonathan L. French, Sc.D. at 2020 American Conference on Pharmacometrics (ACoP11) virtual meeting. 11 November 2020.

Markov models at the intersection of pharmacometrics and health economics

Presentation by Marc Gastonguay, Ph.D. at 2020 American Conference on Pharmacometrics (ACoP11) virtual meeting. 11 November 2020.

Quantification of the Impact of Partition Coefficient Prediction Methods on PBPK Model Output Using a Standardized Tissue Composition

Utsey, Kiersten, Madeleine S. Gastonguay, Sean Russell, Reed Freling, Matthew M. Riggs, and Ahmed Elmokadem. 2020. Drug Metabolism and Disposition: The Biological Fate of Chemicals, July. https://doi.org/10.1124/dmd.120.090498.

The confluence of Statistical and Pharmacometric Approaches for Benefit Risk Analysis: a case study using Bayesian joint models for safety and efficacy

Presented by Jonathan French, Sc.D., at the American Conference on Pharmacometrics (ACoP10) during the tutorial: The Role of Pharmacometrics in Advancing Quantitative Benefit-Risk Assessments for Drug Review and Approval. 24 Oct 2019

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.

Considerations and Future Directions for the Development of Open-Source, Public License, Pharmacometric Software

Presented by Marc Gastonguay, Ph.D. at ACCP Annual Meeting September 17, 2019.

Solving the Package Management Puzzle

Pastoor, Devin. Presentation at R/Pharma. Cambridge, MA. 22 Aug 2019.

Prediction of maternal-fetal exposures of CYP450-metabolized drugs using physiologic pharmacokinetic modeling implemented in R and mrgsolve

Gastonguay, Madeleine. Presentation at R/Pharma. Cambridge, MA. 23 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.

Torsten: Stan functions for pharmacometric applications. New functionality including within chain parallel computation.

Zhang Y,  Gillespie W. Poster presented at 2019 Population Approach Group in Europe (PAGE). Stockholm, Sweden. 13 June 2019. Abstract IV-29.

Causa Nostra: the potentially legitimate business of drawing causal inferences from observational data

Rogers JA. CPT Pharmacometrics Syst Pharmacol [Internet]. 2019 Feb 14; Available from: http://dx.doi.org/10.1002/psp4.12395

Causa Nostra: The potentially legitimate business of drawing causal inferences from observational data

Rogers JA. Presentation at 2018 American Conference on Pharmacometrics (ACoP9). San Diego, CA. 9 Oct 2018.

A physiologically-based pharmacokinetic model for Voriconazole explores differences in pharmacokinetics between adults and children

Elmokadem A. Poster presented at 2018 American Conference on Pharmacometrics (ACoP9). San Diego, CA. 9 Oct 2018. Abstract #M-003.

Evaluating the impact of estimated partition coefficients by different methods using a unified PBPK model

Elmokadem A. Lightning talk presented at International Society of Pharmacometrics New England 2018. Cambridge, MA. 12 Sep 2018.

Development of an open and general physiologically-based pharmacokinetic model to predict maternal-fetal exposures for drugs metabolized by CYP isoenzymes

Gastonguay MS. Presented at the R/Medicine 2018 Conference. New Haven, CT. 8 Sep 2018.

Bayesian inference with partial differential equations using Stan

Zhang Y, Gillespie WR, Minjie Zhu. Poster presented at StanCon. Helsinki, Finland. 30 Aug 2018.

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.

R as the core technology to support modeling and simulation in pharma research, development, and post approval activities

Gastonguay MR. Lightning Talk presented at the 1st annual R/Pharma conference. Boston, MA. 16 August 2018.

Assisting pharmacometric simulation with the use of Shiny

Kang J. Lightning Talk presented at the 1st annual R/Pharma conference. Boston, MA. 16 August 2018.

Moving fast without breaking things: navigating the R ecosystem in an enterprise environment

Pastoor D. Invited Talk presented at the 1st annual R/Pharma conference. Boston, MA. 15 August 2018.

Torsten: Stan functions for pharmacometrics applications

Gillespie WR. Presented at Stan for Pharmacometrics. Paris, France. 24 July 2018.

The pharmacokinetics and pharmacodynamics of buprenorphine in neonatal abstinence syndrome

Moore JN, Gastonguay MR, Ng CM, Adeniyi-Jones SC, Moody DE, Fang WB, Ehrlich ME, Kraft WK. Clin Pharmacol Ther. 103 (6) 1029-1037; June 2018

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana

Vujkovic M, Bellamy SL, Zuppa AF, Gastonguay MR, Moorthy GS, Ratshaa B, Han X, Steenhoff AP, Mosepele M, Strom BL, Bisson GP, Aplenc R, Gross R. Pharmacogenomics J. doi: 10.1038/s41397-018-0028-2. Epub June 1, 2018.

A joint design for functional data with application to scheduling ultrasound scans

Park SY, Xiao L, Wilbur JD, Staicu A, Jumbe NL. Computational Statistics and Data Analysis. 122:101-114. June 2018

Bayesian data analysis using Stan/Torsten for pharmacometric applications

Gillespie WR. Presented at the Midwest Biopharmaceutical Statistics Workshop (MBSW), Indianapolis, IN, May 2018.

Modeling methods for analyzing tumor dynamic data from basket trials

Ocampo-Pelland AS, French JL.  Presented at the 8th American Conference on Pharmacometrics (ACoP), Fort Lauderdale, FL, October 2017.

Post-approval decision making supported by modeling and simulation based on a variety of data sources

Gastonguay MR. Presented at the 8th American Conference on Pharmacometrics (ACoP), Fort Lauderdale, FL, October 2017.

Gaining efficiency by combining analytical and numerical methods to solve ODEs: Implementation in Stan and application to Bayesian PK/PD modeling

Margossian C and Gillespie WR.  Presented at the 8th American Conference on Pharmacometrics (ACoP), Fort Lauderdale, FL, October 2017.

Points to consider when making inferences about covariates

Gastonguay MR. Presented at the 8th American Conference on Pharmacometrics (ACoP), Fort Lauderdale, FL, October 2017.

Theory, empiricism, and a vision for the continued growth of pharmacometrics

Gastonguay MR.  The International Society of Pharmacometrics Lewis B. Sheiner Award Lecture presented at the 8th American Conference on Pharmacometrics (ACoP), Fort Lauderdale, FL, October 15, 2017.

A joint optimal design for functional data with application to scheduling ultrasound scans

Park SY, Xia L, Wilbur J, Staicu AM, Jumbe NL.  Paper presented at: Eastern North American Region (ENAR) Spring Meeting of the International Biometric Society, March 2017, Washington, DC.

Stan functions for Bayesian pharmacometric modeling

Margossian CC and Gillespie WR.  Presented at the 7th American Conference on Pharmacometrics (ACoP), Bellevue, WA; October 2016.

MBMA of combined individual and aggregate data: strategies and issues

Gillespie WR. Presented at the 7th American Conference on Pharmacometrics (ACoP), Bellevue, WA; October 2016.

Bayesian pharmacometric modeling with BUGS, NONMEM, and Stan

Gillespie WR.  Presented at the 7th American Conference on Pharmacometrics (ACoP), Bellevue, WA; October 2016.

Interactive simulation-based assessment of “go/no-go” decision making in Duchenne muscular dystrophy clinical trials

Hajjar J, French JL, Gastonguay MR.  Presented at the 7th American Conference on Pharmacometrics (ACoP), Bellevue, WA; October 2016.

Automation of Population Pharmacokinetic-Pharmacodynamic Modeling Reports Using the RShiny Application: TFL Generator

Melhem M, Polhamus D, Lau T, Chen P, Narayanan A, Clements JD, Gibbs J, Seegan G.  Presented at the 7th American Conference on Pharmacometrics (ACoP), Bellevue, WA; October 2016.

Prototype Stan functions for Bayesian pharmacometric modeling

Gillespie WR and Margossian CC.  Presented at Stan for Pharmacometrics Day, Paris 22 Sep 2016.

Facilitating clinical trial simulation in Alzheimer’s disease using the CAMD IPD, literature summary level data, and the ‘adsim’ R package

Polhamus D.  Presented at The Joint Statistical Meetings (JSM), August, 2016.

Optimal design for sampling functional data

Park SY, Xia L, Wilbur J, and Staicu, AM.  Presented at The Joint Statistical Meetings (JSM), August 2016, Chicago, IL; Abstract 319197.

Comparisons of multiple exposure-response methodologies in oncology.

Polhamus D, French J, Chen SC, Wang B, Li C, Lu D, Girish S, Jin J, Quartino A.  Presented at the Annual Meeting of the Population Approach Group in Europe (PAGE), Lisboa, June 2016.

A case study in comparing cognitive development across populations

French JL, Racine A, van Buuren S, Haggstrom J.  Presented at the Annual Meeting for the Population Approach Group in Europe (PAGE), Lisboa, June 2016.

Zika microcephaly cutoffs revisited: A study of Non-parametric methods in fetal growth

Wilbur JD, Ohuma E, Xiao L, Mouksassi S, Hafen R.  Presented at the Annual Meeting of the Population Approach Group in Europe (PAGE), Lisboa, June 2016.

The role of simulation in assessing extrapolation assumptions

Gastonguay MR.  Presented at the Quantitative Assessment of Assumptions to Support Extrapolation of Efficacy in Pediatrics: FDA – U Maryland CERSI Cosponsored Workshop.  FDA. June 1, 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.

Big Data: Challenges and opportunities for clinical pharmacology

Flockhart D, Bies RR, Gastonguay MR, Schwartz SL.  Br J Clin Pharmacol. 2016 May;81(5):804-6.

Model-based meta-analysis for development of a population-pharmacokinetic (PPK) model for Vitamin D3 and its 25OHD3 metabolite using both individual and arm-level data

Ocampo-Pelland AS, Gastonguay MR, French JF, Riggs MM.  J Pharmacokinet Pharmacodyn. 2016 Apr;43(2):191-206.

Facilitating cardiovascular safety exposure-response modeling in early-phase clinical studies with the cardioModel package for R

Conrado DJ, Hather GJ, Chen D, Denney WS. Facilitating Cardiovascular Safety Exposure-Response Modeling in Early-Phase Clinical Studies with the cardioModel Package for R.  Presented at the 6th American Conference on Pharmacometrics (ACoP), Arlington, VA, October 2015

A pharmacometrician’s perspective for utilization of big data

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

A modeling and simulation framework for exposure-response analysis in oncology: comparison and considerations of multiple methodologies

Polhamus D, French J, Chen S-C, Wang B, Li C, Lu D, Girish S, Jin J, Quartino A.  Presented at the 6th American Conference on Pharmacometrics, Arlington, VA; October 2015.

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.

Trends in the application of pharmacometric modeling and simulation in the development of orphan drugs in the 21st century

Hajjar J, Fisher J, Gastonguay MR.  Presented at the 6th American Conference on Pharmacometrics (ACoP), Arlington, VA; October 2015.

Implementing FDA specifications in R for submission of analysis datasets

Bergsma T and Pivirotto S.  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.

A priori identifiability of target-mediated drug disposition models and approximations

Eudy RJ, Riggs MM, Gastonguay MR. AAPS J. 2015 Sep;17(5):1280-4.

Model-based meta-analysis for development of a population pharmacokinetic (PPK) model for vitamin D3 and its 25OHD3 metabolite

Ocampo-Pellend AS, Gastonguay, French JL, Riggs MM. Presented at the Annual Meeting of the Population Approach Group in Europe (PAGE), Hersonissos, 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).

Modeling and simulation for medical product development and evaluation: highlights from the FDA-C-Path-ISOP 2013 workshop

Romero K, Sinha V, Allerheiligen S, Danhof M, Pinheiro J, Kruhlak N, Wang Y, Wang SJ, Sauer JM, Marier JF, Corrigan B, Rogers J, Lambers Heerspink HJ, Gumbo T, Vis P, Watkins P, Morrison T, Gillespie W, Gordon MF, Stephenson D, Hanna D, Pfister M, Lalonde R, Colatsky T. Journal of Pharmacokinetics and Pharmacodynamics, 2014 Dec;41(6):545-52. doi: 10.1007/s10928-014-9390-0.

Web-based software for real-time simulation-assisted trial design in Alzheimer’s disease

Polhamus DG, Kang J, Rogers JA, and Gastonguay MR. Presented at the 7th Annual Clinical Trials on Alzheimer’s Disease (CTAD), November 2014.

Establishing a priori identifiability of target mediated drug disposition models

Eudy RJ and Gastonguay MR. Presented at the 5th American Conference on Pharmacometrics (ACoP), Las Vegas, NV, October 2014.

Self-auditing data tables for R

Bergsma T and Pivirotto S.  Presented at the 5th American Conference on Pharmacometrics (ACoP), Las Vegas, NV, October 2014.

Elastic cloud computing in pharmacometrics: Usage data and strategies for efficient workflows

Knebel W, Gastonguay M, Polhamus D, Hane JT. Presented at the Annual Meeting of the Population Analysis Group in Europe (PAGE), Alicante, Spain; June 2014; Abstract I-55.

Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations

J. S. Gewandter, R. H. Dworkin, D. C. Turk, M. P. McDermott, R. Baron, M. R. Gastonguay, I. Gilron, N. P. Katz, C. Mehta, S. N. Raja, S. Senn, C. Taylor, P. Cowan, P. Desjardins, R. Dimitrova, R. Dionne, J. T. Farrar, D. J. Hewitt, S. Iyengar, G. W. Jay, E. Kalso, R. D. Kerns, R. Leff, M. Leong, K. L. Petersen, B. M. Ravina, C. Rauschkolb, A. S. C. Rice, M. C. Rowbotham, C. Sampaio, S. H. Sindrup, J. W. Stauffer, I. Steigerwald, J. Stewart, J. Tobias, R.-D. Treede, M. Wallace, and R. E. White.  Pain. 2014 Sep;155(9):1683-95. doi: 10.1016/j.pain.2014.05.025. Epub 2014 May 24.

A cloud-based cluster computing platform for pharmacometric applications

Bergsma T, Knebel W, Polhamus D, Hane JT, Gastonguay MR. Presented at the 4th American Conference on Pharmacometrics (ACoP), Ft. Lauderdale; May 2013.

Facilitating pharmacometric workflow with the metrumrg package for R

Bergsma TT, Knebel W, Fisher J, Gillespie WR, Riggs MM, Gibiansky L, Gastonguay MR. Comput Methods Programs Biomed. 2013 Jan;109(1):77-85.

Sumo: An authenticating web application with an embedded R session

Bergsma TT and Smith MS. The R Journal; June 2012, Vol. 4 Issue 1, p60-63.

From evidence synthesis to trial optimization: The adsim package for model-based simulation in Alzheimer’s disease

Polhamus D, Rogers JA, Gillespie W, French J, and Gastonguay M.  Presented at the 21st Annual Meeting of the Population Approach Group Europe (PAGE), Venice, Italy, June 2012, Abstract 2580.

Building a scalable pharmacometrics platform in the cloud

Hane J and Kraut A.  Presented at BioIT World Conference and Expo, Boston, MA; April 23-25, 2012.

The value of evidence synthesis: Model-based meta-analysis based on the CAMD database, the ADNI AD cohort data, and literature meta-data

Rogers JA, Polhamus D, Ito K, Qiu R, Gillespie W, Corrigan B. Presented at the 2012 American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting, National Harlbor, MD; March 2012.

Two guys and a credit card: Metrum’s Amazon cloud makeover – A case study in transferring a life sciences IT infrastructure fully into the cloud

Davies K.  Bio-IT World, Feb 14, 2012.

Full covariate models as an alternative to methods relying on statistical significance for inferences about covariate effects: A review of methodology and 42 case studies 

Gastonguay MR.  Presented at the 20th Annual Meeting of the Population Approach Group Europe (PAGE),  Athens, Greece,  June 2011. Abstract 2229.

Population pharmacokinetic/pharmacodynamic model of subcutaneous adipose 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) activity after oral administration of AMG 221, a selective 11β‐HSD1 inhibitor

Gibbs JP, Emery MG, McCaffery I, Smith B, Gibbs MA, Akrami A, Rossi J, Paweletz K, Gastonguay MR, Bautista E, Wang M, Perfetti R, Daniels O.  J Clin Pharmacol. 51(6):830-41. June 2011.

Strategic data handling for pharmacometrics

Bergsma T. Presented at ACOP; April 2011; San Diego, CA.

Systematic review of versioned files for modeling and simulation quality control: the“review” R package

Bergsma T, Fisher J, Gastonguay MR, Hane J, Knebel W, Riggs MM, Rogers JA. Presented at ACOP; April 2011; San Diego, CA.

Population pharmacokinetic modeling of pantoprazole in pediatric patients from birth to 16 years

Knebel W, Tammara B, Udata C, Comer G, Gastonguay MR, Meng X.  J Clin Pharmacol. 51(3):333-45. March 2011.

A longitudinal dose-response model for the progression of alzheimers disease, based on a combination of summary-level and patient-level data

Rogers JA, Ito K, Gillespie WR, Corrigan BW, Gastonguay MR. Presented at the Fourth Annual Bayesian Biostatistics Conference, Houston, TX. 26–28 January 2011.

Quantifying uncertainty in predictions of hepatic clearance

Rogers JA, Wilbur J, Cole S, Bernhardt PW, Bupp JL, Lennon MJ, Langholz N, Steiner CP. Statistics in Biopharmaceutical Research. 3(4):515-525. (2011)

Development of mechanistic/multiscale/systems biology models in clinical pharmacology and translational research: do the challenges outweigh the potential benefits?

Riggs MM.  2010 AAPS Clinical Pharmacology and Translational Research (CPTR) Open Forum; 16 November 2010.

Pharmacometrics as a discipline is entering the “industrialization” phase: standards, automation, knowledge sharing, and training are critical for future success

Romero K, Corrigan B, Tornoe CW, Gobburu JV, Danhof M, Gillespie WR, Gastonguay MR, Meibohm B, Derendorf H. J Clin Pharmacol. 50(9 Suppl):9S-19S. September 2010.

Defining the future of pharmacometrics: the American Society of Pharmacometrics

Pfister M, Brundage RC, Gastonguay MR, Miller R, Tannenbaum SJ, D’Argenio DZ. J Clin Pharmacol. ;50(9 Suppl):158S. September 2010.

ACoP: the tools, carpenters, and architects building the discipline of pharmacometrics

Brundage RC, Pfister M, D’Argenio DZ, Gastonguay MR, Miller R, Tannenbaum SJ. J Clin Pharmacol. 50(9 Suppl):7S-8S. September 2010.

Comparison of MCMC simulation results using NONMEM 7 or WinBUGS with BUGSModelLibrary

Gastonguay MR, Gillespie WR, Bauer RJ. Presented at PAGE 2010. Berlin, Germany. 8–11 June 2010

Utilizing NONMEM 7 and the intel fortran compiler in a distributed computing environment

Knebel W, Bergsma TT, Dagdigian C, Hane J, Gastonguay MR. Presented at PAGE 2010, 19th Meeting, Berlin, Germany, June 8–11, 2010.

Predicting nonlinear changes in BMD over time using a physiologically-based mathematical model

Peterson MC and Riggs MM. Presented at American Association of Pharmaceutical Scientists National Biotechnology Conference, Update on Quantitative Systems and Disease Models for Biologics. Mini–Symposium. San Francisco, CA; May 2010.

Population pharmacokinetics of dexmedetomidine in infants after open heart surgery

Su F, Nicolson SC, Gastonguay MR, Barrett JS, Adamson PC, Kang DS, Godinez RI, Zuppa AF. Anesth Analg. 110(5):1383-92. May 2010.

Multiscale modeling: the quantitative integration of systems biology, clinical pharmacology and translational research

Riggs MM. Presented at American Association of Pharmaceutical Scientists National Biotechnology Conference, Update on Quantitative Systems and Disease Models for Biologics. Mini–Symposium. San Francisco, CA; May 2010.

An issue in controlling the type 1 error rate with adaptive designs using time-to-event endpoints

Rogers JA. Presented at 3rd Annual FDA/MTLI Medical Device and IVD Statistics Workshop. 28 April 2010.

Comparative performance of bayesian markov chain monte carlo and maximum likelihood population estimation methods when applied to nonlinear pharmacokinetics of monoclonal antibodies

Dirks N, Gastonguay MR, Gillespie WR, Knebel W, Riggs MM, Panetta JC, and Meibohm B. Presented at ASCPT 111th Annual Meeting, March 17-20, 2010.

Exposure-response modeling and clinical trial simulation of the effect of tolterodine on QT intervals in healthy volunteers

Sweeney KR, Gastonguay MR, Benincosa L, Cronenberger CL, Glue P, Malhotra BK. Drug Discov Ther. 4(1):44-53. February 2010.

Quantitative assessment of exposure–response relationships for the efficacy and tolerability of varenicline for smoking cessation

Ravva JP, Gastonguay MR, French JL, Tensfeldt TG, and Faessel HM. Clinical Pharmacology & Therapeutics. 87(3):336-44. January 2010.

Population pharmacokinetics of intravenous ondansetron in oncology and surgical patients aged 1-48 months

Mondick JT, Johnson BM, Haberer LJ, Sale ME, Adamson PC, Coté CJ, Croop JM, Russo MW, Barrett JS, Hoke JF. Eur J Clin Pharmacol. 66(1):77-86. January 2010.

The impact of missing data on model evaluation

Gastonguay MR. Presented at ACOP 2009. 6 October 2009; Mashantucket, CT.

Population dose-response model for ADAS-cog ccores in patients with alzheimers disease by meta-analysis of a mixture of summary and individual data

Gillespie WR, Rogers JA, Ito K, Gastonguay MR. Presented at ACOP 2009. October 4-7, 2009; Mashantucket, CT.

Prototype model library for bayesian pharmacokinetic/pharmacodynamic (PKPD) modeling in WinBUGS

Gillespie B, Gastonguay MR. Presented at ACOP 2009. October 4-7, 2009; Mashantucket, CT.

A systems biology model to describe long-term bone remodeling effects of estrogen in menopausal and postmenopausal women

Riggs MM, Peterson MC, Gastonguay MR. Presented at ACOP 2009. October 4-7, 2009; Mashantucket, CT.

Preliminary population pharmacokinetic modeling of PF-04360365, a humanized anti-amyloid monoclonal antibody, in patients with mild-to-moderate alzheimer’s disease

Nicholas T, Knebel W, Gastonguay MR, Bednar MM, Billing B, Landen JW, Kupiec JW, Corrigan B, Laurencot R, Zhao Q. Poster presented at the ICAD 2009 Annual Meeting; July 11–16, 2009; Vienna, Austria.

Population dose-response model for ADAS-cog scores in patients with alzheimer’s disease by meta-analysis of a mixture of summary and individual data

Gillespie B, Rogers JA, Ito K, Gastonguay MR. ASCPT 110th Annual Meeting, March 18-21, 2009; Washington D.C.

Population pharmacokinetic modeling of epoetin delta in pediatric patients with chronic kidney disease

Knebel W, Palmen M, Dowell JA, Gastonguay M. J Clin Pharmacol. 48(7):837-48. July 2008.

Population pharmacokinetic modeling of fosamprenavir in pediatric HIV-infected patients

Fisher J, Gastonguay MR, Knebel W, Gibiansky L, Wire MB. Poster presented at the American Conference on Pharmacometrics. March 9-12 2008; Tucson, Arizona.

Use of rpad, an open-source, interactive, web-based analysis program, for visualization during model-based drug development of adipiplon, a GABAA receptor partial agonist under investigation for the treatment of insomnia

Riggs MM, Bergsma TT, Gillespie WR, Gastonguay MR, Sprenger KJ. Poster presented at the American Conference on Pharmacometrics. March 9-12 2008; Tucson, Arizona.

Open source software tools for parallel computation of multiple MCMC chains with WinBUGS

Gillespie WR, Gastonguay MR, Knebel W, Georgalis G. Poster presented at the American Conference on Pharmacometrics. March 9-12 2008; Tucson, Arizona.

Facilitating the pharmacometrics work-flow with the mItools r package

Knebel W, Bergsma T, Fisher J, Georgalis G, Gibiansky L, Gillespie WR, Riggs MM, Gastonguay MR. Poster presented at the American Conference on Pharmacometrics. March 9-12 2008; Tucson, Arizona.

Bayesian approaches to mixed effects models for ordered categorical data

Gillespie WR, Gastonguay MR, Knebel W. Presented at the AAPS Annual Meeting; November 2007; San Diego, CA.

Population pharmacokinetic-pharmacodynamic modeling of istradefylline in patients with parkinson’s disease

Knebel W, Rao N, Bergsma T, Gastonguay M, Mori A, Uchimura T, Allenby K, Dvorchik B, Sussman N, Chaikin P. Presented at ACCP; October 14-17, 2007; Denver, CO.

Quantitative assessment of exposure-response relationships for the efficacy and tolerability of varenicline for smoking cessation

Rawa P, Faessel H, Gastonguay MR, Tensfeldt TG, Reeves K. Clin Pharmacol Ther. 81(S1) March 2007; Abstract PII-73: S72.

Exposure-response (PK-PD) applied to model-based drug development: A case study of drug x

Riggs M. FDA/Industry Statistics Workshop. 29 September 2006; Washington D.C.; Parallel Session 14: Case Studies in Modeling and Simulation, Abstract.

Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy

Agoram B, Heatherington AC, Gastonguay MR. AAPS Journal. 8(3), September 2006. doi: 10.1208/aapsj080364

Acknowledging and incorporating uncertainty in model-based inferences

Gastonguay MR, Gibiansky L. Presented at the ECPAG Conference. July 24-26, 2006; Rockville, MD; Workshop Poster Session, Abstract.

Acknowledging parameter uncertainty in the simulation-based design of an actinomycin-D pharmacokinetic study in pediatric patients with Wilms’ Tumor or rhabdomyosarcoma

Mondick JT, Gibiansky L, Gastonguay MR, Veal GJ, Barrett JS. Presented at PAGE 2006. June 14-16, 2006; Brugge/Bruges, Belgium; Abstract 938.

R/NONMEM Toolbox for simulation from posterior parameter (uncertainty) distributions

Gibiansky L and MR Gastonguay. Presented at PAGE 2006. June 14-16, 2006; Brugge/Bruges, Belgium; Abstract 958.

Acknowledging parameter uncertainty by simulating from posterior distributions with NONMEM and R

Gastonguay MR, Gibiansky L. Presented at the MUFPADA Annual Meeting. May 2-3, 2006; Ann Arbor, MI; Abstract.

NMQual: A tool to automate installation and facilitate qualification of NONMEM

Knebel B, Bergsma T, Gibiansky L, Hane JT, Gastonguay MR. Presented at PAGE Annual Meeting. June 16-17, 2005; Pamplona, Spain; Abstract 779.

Modeling and simulation guided design of a pediatric population pharmacokinetic trial for hydromorphone

Gastonguay MR, El-Tahtawy A. The AAPS Journal. 7(S2), June 2005. Abstract W5318.

Effect of NONMEM minimization status and number of replicates on bootstrap parameter distributions for population pharmacokinetic models: a case study

Gastonguay MR, El-Tahtawy A. Clinical Pharmacology and Therapeutics. 77(2), P2-P2; February 5, 2005.

Population pharmacokinetic model of sedative doses of GPI 15715 and propofol liberated from GPI15715

Gibiansky E, Gibiansky L, Enriquez J. Clinical Pharmacology and Therapeutics. 77(2), P48-P48; February 5, 2005.

NONMEM Non-influential correlated ETAs bug and how to fix it

Gibiansky L. Presented at AAPS Annual Meeting: PPDM Poster-Podium Session, November 10, 2004; Baltimore, MD.

Estimation and prediction of chaotic pharmacodynamic systems using nonlinear mixed-effects models: the butterfly effect

Gastonguay MR, Bies R. The AAPS Journal. 6(S1) (2004); Abstract W4353, 2004.