Other

Impact of Model-Informed Drug Development on Drug Development Cycle Times and Clinical Trial Cost

While the application of MIDD has grown, there have been no clear examples across programs to demonstrate its value at the portfolio level. This manuscript offers a methodology and examples to demonstrate MIDD value in terms of time and cost savings.

Agents for Change: Artificial Intelligent Workflows for Quantitative Clinical Pharmacology and Translational Sciences

Explore real-world applications of LLM-driven multi-agentic workflows in clinical pharmacology, pharmacometrics, and translational sciences. These semi-autonomous AI systems are designed to streamline decision-making, optimize workflows, and ultimately accelerate the development of safe and effective medicines for patients in need. 

Scientific Project Management (SPM) to Enhance Model-Informed Drug Development.

Presented at ACoP 2024. This poster describes the scientific project management role in MIDD and it’s benefits over a traditional project management approach.

Reinforcement Learning for Pharmacometrics: A Proof of Concept and Future Directions.

Presented at ACoP 2024. A proof-of-concept was conducted using deep reinforcement learning to optimize vancomycin dosing based on predicted PK profiles. The reinforcement learner was able to produce dose recommendations that (on average) exceeded the standard-of-care recommended dose, and future opportunities for using reinforcement learning within pharmacometrics are vast with a large potential for impact through personalized dosing.

Pharmacometric-Pharmacoeconomic Modeling and Simulation in Atopic Dermatitis: Informing Early Drug Development Decisions for a Hypothetical New Therapeutic.

Presented at ACoP 2024. Early drug development decision making, such as the definition and assessment of target product profile characteristics, rarely includes pharmacoeconomic (PE) considerations. The disciplines of phamacometrics (PM) and PE are closely aligned and intersect at the goal of a quantitative understanding of the system. Connection of these two disciplines is a logical extension of typical PM objectives and should lead to a more complete and accurate understanding of the probability of success for new therapeutics.

Longitudinal Joint Modeling of Modified Mayo Score and Dropout in Patients with Moderate to Severely Active Ulcerative Colitis.

Presented at ACoP 2024. A longitudinal joint model of modified mayo scores and dropout for patients with ulcerative colitis receiving etrasimod was developed in two Phase 3 studies. This poster presents the development of the model in a Bayesian framework, illustrating the ability of the model to adequately describe changes in efficacy scores in the presence of a spike in dropout at the end of a maintenance phase.

Gompertz Cure Rate Survival Models with Stan and brms.

Presented at ACoP 2024. A Gompertz distribution is implemented in Stan and brms to enable cure rate survival modeling. The Gompertz brms family can be used to model exposure-response data in a Bayesian framework where a proportion of the population never experiences the event of interest.

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.

Oral progesterone-mediated attenuation of ibutilide-induced qt interval lengthening in premenopausal and postmenopausal women: population pharmacokinetic/ pharmacodynamic model.

Presented at ASCPT Annual Meeting 2024. Our model adequately characterized ibutilide PK and its QT interval lengthening effect. The higher Emax suggests more ibutilide induced QT lengthening in premenopausal women. The difference of Emax between group A and B reflects potential progesterone effect.

Exposure–efficacy relationship of vedolizumab subcutaneous and intravenous formulations in Crohn’s disease and ulcerative colitis

This posthoc analysis of the GEMINI and VISIBLE studies in ulcerative colitis (UC) and Crohn’s Disease (CD) assessed exposure−efficacy of vedolizumab intravenous (IV) and subcutaneous (SC).

Confounded exposure metrics

Exposure-response (E-R) modeling frequently relies on the use of exposure metrics that summarize drug concentrations over time. This research presents simulations to demonstrate that certain commonly used exposure metrics, including average concentration up to an event time, are likely to lead to causal confounding under the very conditions that motivate their use.

Connecting ISoP with Statisticians: An Introduction to the Biopharmaceutical Section of the American Statistical Association

Presented at ACoP14. The American Statistical Association (ASA) comprises regional chapters and specialized sections, including the Biopharmaceutical Section (BIOP), established in 1981. BIOP focuses on applying statistics to drug development, biologics, devices, and related technologies in humans and animals. Initially created to connect ISoP and ASA, SxP employs innovative statistical methods to address similar inquiries, despite using distinct terminologies and assumptions in modeling. This poster offers insight into BIOP’s history, objectives, organization, and avenues for involvement or contacting its members.

Training the next generation of pharmacometric modelers: a multisector perspective

The demand for pharmacometricians has outpaced academic supply, with increasing investments in on-the-job training. Despite growth in academic programs, the expanding scope of pharmacometrics and emerging fields like machine learning pose challenges. Leading experts from diverse sectors offer recommendations for effectively training future pharmacometricians, ensuring their ability to navigate this evolving discipline.

Open-Source Bayesian Hierarchical PBPK Modeling in Julia

Demonstrates a Bayesian analysis workflow in Julia for an ODE-based model using PBPK modeling as an illustrative example.

Disease Trajectory modeling of SLE clinical endpoints using a Latent Variable Model: Analysis of Pooled Patient-Level Placebo (Standard-of-Care) Data

Kosalaram Goteti, Jonathan French, Ramon Garcia, Ying Li, Florence Casset-Semanaz, Aida Aydemir, Robert Townsend, Cristina Vazquez Mateo, Matthew Studham, Oliver Gunther, Amy Kao, Marc Gastonguay, Pascal Girard, Lisa Benincosa, Karthik Venkatakrishnan. Poster presented at 12th American Conference on Pharmacometrics (ACoP), November 2021. Poster PIB-011.

A Population Pharmacokinetic Model and Exposure-Response Model of Repeated Time Event (RTTE) to Justify a Dose Increase in Patients with Sickle Cell Disease

Rena Byrne, Rahul Ballal, Ana Ruiz-Garcia. Poster presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October – November 2 2022. Poster T-016

An Empirical Approach to Identifying Electrophysiological Correlates of Topiramate-Related Working Memory Impairment Using Pharmacokinetic-Pharmacodynamic Modeling

Samuel P. Callisto, Christopher M. Barkley, Mark Fiecas, Richard Brundage, Angela K. Birnbaum, Susan E. Marino. Poster presented at 2022 WCOP. March 29 – April 1 2022. Poster 35.

A model-based analysis to guide gonadotropin-releasing hormone receptor antagonist use for management of endometriosis

Pohl O, Baron K, Riggs M, French J, Garcia R, Gotteland JP. Br J Clin Pharmacol. 2021; 1– 13. doi:10.1111/bcp.15171

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.

Impact of Obesity on Brexpiprazole Pharmacokinetics: Proposal for Improved Initiation of Treatment

Bruno CD, Elmokadem A, Housand C, Jordie EB, Chow CR, Laughren T, Greenblatt DJ. Journal of Clinical Pharmacology.  2021;62(1):55-65. doi:10.1002/jcph.1947

Population pharmacokinetic analysis of ulotaront in subjects with schizophrenia

Galluppi GR, Polhamus DG, Fisher JM, Hopkins SC, Koblan KS. CPT Pharmacometrics Syst Pharmacol. Published online July 22, 2021. doi:10.1002/psp4.12692

Welcome to the statistics and pharmacometrics themed issue

French J, Mentré, F. CPT Pharmacometrics Syst. Pharmacol. 2021;10: 273-274. doi:10.1002/psp4.12625

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.

Population pharmacokinetics of vedolizumab in Asian and non-Asian patients with ulcerative colitis and Crohn’s disease.

Okamoto H, Dirks NL, Rosario M, Hori T, Hibi T. Intest Res. 2021;19(1):95-105. doi:10.5217/ir.2019.09167.

Population pharmacokinetics of adalimumab biosimilar adalimumab-adbm and reference product in healthy subjects and patients with rheumatoid arthritis to assess pharmacokinetic similarity.

Kang J, Eudy-Byrne RJ, Mondick J, Knebel W, Jayadeva G, Liesenfeld KH. Br J Clin Pharmacol. 2020 Nov;86(11):2274-2285. doi: 10.1111/bcp.14330.

MID3: Mission Impossible or Model‐Informed Drug Discovery and Development? Point‐Counterpoint Discussions on Key Challenges

Krishnaswami, S., Austin, D., Della Pasqua, O., Gastonguay, M.R., Gobburu, J., van der Graaf, P.H., Ouellet, D., Tannenbaum, S. and Visser, S.A.G. (2020), MID3: Mission Impossible or Model‐Informed Drug Discovery and Development? Point‐Counterpoint Discussions on Key Challenges. Clin. Pharmacol. Ther., 107: 762-772. doi:10.1002/cpt.1788

 

MID3: Mission Impossible or Model‐Informed Drug Discovery and Development? Point‐Counterpoint Discussions on Key Challenges

Krishnaswami, S., Austin, D., Della Pasqua, O., Gastonguay, M.R., Gobburu, J., van der Graaf, P.H., Ouellet, D., Tannenbaum, S. and Visser, S.A. (2020), MID3: Mission Impossible or Model‐Informed Drug Discovery and Development? Point‐Counterpoint Discussions on Key Challenges. Clin. Pharmacol. Ther. Accepted Author Manuscript. doi:10.1002/cpt.1788

M-EASE-2: A Modelling and simulation study conducted to further characterize the efficacy of low-dose Empagliflozin as Adjunctive to inSulin thErapy (M-EASE) in Type 1 Diabetes Mellitus (T1DM)

Johnston C, Riggs MM, Marquard J, Soleymanlou N, Nock V, Liesenfeld, K. Poster presented at 2019 Population Approach Group in Europe (PAGE). Stockholm, Sweden. 13 June 2019. Abstract IV-66.

M-EASE-1: A Modelling and simulation study conducted to further characterize the efficacy of low-dose Empagliflozin as Adjunctive to inSulin thErapy (M-EASE) in Type 1 Diabetes Mellitus

Eudy-Byrne R, Elmokadem A, Riggs MM, Johnston C, Marquard J, Soleymanlou N, Nock V, Liesenfeld K. Poster presented at 2019 Population Approach Group in Europe (PAGE). Stockholm, Sweden. 13 June 2019. Abstract III-02.

The M-EASE Studies: A Modeling and simulation approach to further characterize the efficacy of low-dose Empagliflozin as Adjunctive to InSulin ThErapy in type 1 diabetes

Perkins BA, Soleymanlou N, Rosenstock J, Skyler JS, Laffel LM, Liesenfeld K, Neubacher D, Riggs MM, Johnston CK, Eudy-Byrne RJ, Elmokadem A, George JT, Marquard J, Nock V. Poster presented at American Diabetes Association (ADA) 79th Scientific Sessions 2019. San Francisco, CA. 7-11 June 2019. Abstract 1198-P.

Bayesian data analysis using Stan/Torsten for pharmacometric applications

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

Corrigendum: Exposure-efficacy relationships for vedolizumab induction therapy in patients with ulcerative colitis or Crohn’s disease

Rosario M, French JL, Dirks NL, Sankoh S, Parikh A, Yang H, Danese S, Colombel JF, Smyth M, Sandborn WJ, Feagan BG, Reinisch W, Sands BE, Sans M, Fox I. J Crohns Colitis 12 (4): 510. 2018 Mar 28.

Model-based clinical pharmacology profiling and exposure-response relationships of the efficacy and biomarker of lebrikizumab in patients with moderate-to-severe asthma

Zhu R, Zheng Y, Dirks NL, Vadhavkar S, Jin JY, Peng K, Holweg CTJ, Olsson J, Matthews JG, Putnam WS. Pulmonary Pharmacology & Therapeutics 46: 88–98. 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.

Vedolizumab efficacy exposure–response relationship for ulcerative colitis patients (GEMINI I) based on causal inference analysis

Gastonguay MR, Lasch K, Barocas M, Rosario M, Wilbur JD, Dirks NL, Osterman MT.  Presented at the American College of Gastroenterology Annual Meeting, October, 2016.

Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials

Strand V, Ahadieh S, French J, Geier J, Krishnaswami S, Menon S, Checchio T, Tensfeldt TG, Hoffman E, Riese R, Boy M, Gómez-Reino JJ.  Arthritis Res Ther. 2015 Dec 15;17:362.

PK-PD analysis of PASI with data at boundary: BI 655066, an anti-IL-23A mAb for the treatment of psoriasis

Lalovic B, Rogers JA, French J, Flack M. PK-PD Analysis of PASI with Data at Boundary: BI 655066, an Anti-IL-23A mAb for the Treatment of Psoriasis.  Presented at the 6th American Conference on Pharmacometrics (ACoP), Arlington, VA, October 2015

Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease

Rosario M, Dirks NL, Gastonguay MR, Fasanmade AA, Wyant T, Parikh A, Sandborn WJ, Feagan BG, Reinisch W, Fox I.  Aliment Pharmacol Ther. 2015 Jul;42(2):188-202.

Performance of Cpred/Cobs concentration ratios as a metric reflecting adherence to antidepressant drug therapy

Feng Y, Gastonguay MR, Pollock BG, Frank E, Kepple GH, Bies RR.  Neuropsychiatr Dis Treat. 7:117-25. 16 March 2011.

Clinical trial simulation to compare adaptive and fixed designs for a phase 3 clinical trial of Nacystelyn® (L-Lysine-N-acetyl-L-cysteinate) for cystic fibrosis

Rogers JA, Riggs MM, Coffiner M, Gillespie WR, Burford R, Vanderbist F, De Niet S, Gastonguay MR. ACOP 2009. October 4–7, 2009; Mashantucket, CT.

Model-based drug development: optimization of AQUAVAN® injection dosing for minimal-to-moderate sedation

Gibiansky E, Gibiansky L. Presented at PAGE 2006. June 14-16, 2006; Brugge/Bruges, Belgium; Abstract 959.

The importance of the simulation expectation as a goodness of fit diagnostic for categorical population pharmacodynamic models

Gastonguay MR, Hane JT. The AAPS Journal. 6(S1) (2004); Abstract W4355.

A full model estimation approach for covariate effects: inference based on clinical importance and estimation precision

Gastonguay MR. The AAPS Journal. 6(S1) (2004); Abstract W4354.