Evaluating Conditional Exchangeability Assumptions for Bayesian Borrowing, With Application to Pediatric Extrapolation

Presented at the Graybill Conference 2024. Dr. Jim Rogers from MetrumRG as he demonstrates the application of causal selection diagrams as a statistical consulting tool for Bayesian prior elicitation. Bayesian dynamic borrowing is an increasingly important methodology in pediatric extrapolation, and its successful application requires quantitative scientists who can bridge the gap between qualitative notions of “similarity” and formal statistical notions of “exchangeability.”

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.

Adaptive Buprenorphine Dose Simulations In Infants with NOWS (Neonatal Opioid Withdrawal Syndrome).

Presented by Dr. Rena Byrne at the 13th Annual Indiana CTSI Disease and Therapeutic Response Modeling Symposium, February 2024.
View presentation recording.

Population Pharmacokinetic (PK) and Exposure-Response (ER) Analysis of Empagliflozin in Pediatric Patients with Type 2 Diabetes Mellitus (T2DM)

Presented at ACoP14. Empagliflozin, effective for type 2 diabetes in adults and children, underwent Study 1218.91 to assess its safety and efficacy over 26 weeks (with potential extension to 52 weeks) in children and adolescents. Using pediatric data from this study, researchers re-evaluated empagliflozin’s models in a Bayesian framework. Results showed similar drug exposure between children and adults at a 10 mg dose. At week 26, pediatric patients displayed a slightly larger but variable decrease in A1c compared to adults. This Bayesian method allowed insights into empagliflozin’s effects in children, drawing from knowledge gained in adult studies.

Population Pharmacokinetic and Exposure-Response Analysis of Linagliptin in Pediatric Patients with Type 2 Diabetes Mellitus

Presented at ACoP14. This study assessed linagliptin’s effectiveness and safety in children and adolescents with type 2 diabetes over 26 weeks, potentially extending to 52 weeks. The study re-evaluated models developed for adults and adolescents to understand linagliptin’s impact on pediatric patients’ HbA1c levels. Results indicated slightly higher and more varied linagliptin exposure in children compared to adults at a 5 mg dose. Although pediatric patients had a smaller and variable HbA1c reduction versus adults at week 26, the Bayesian approach helped characterize linagliptin’s effects in children based on limited data, borrowing insights from adult studies.

Bayesian Borrowing in the DINAMO Pediatric Study using Informative Priors Derived from Model-based Extrapolation

Presented at ACoP14. The DINAMO study assessed empagliflozin and linagliptin’s effectiveness and safety in treating type 2 diabetes in children. Using prior models based on adult data, the study predicted these medications’ effects in younger populations following FDA guidelines. Employing a Bayesian analysis with robust prior specifications, the study justified its approach by considering factors like weight, kidney function, age, race, and gender when extrapolating adult outcomes to pediatric populations.

Population-Based Pharmacodynamic Modeling of Omalizumab in Pediatric Patients with Moderate to Severe Persistent Inadequately Controlled Allergic Asthma

The objective of this study was to quantitatively characterize the relationship between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) in pediatrics using a population-based pharmacodynamic model.

Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda

Katherine Kay, Justin Goodwin, Hanna Ehrlich, Joyce Ou, Tracey Freeman, Kaicheng Wang, Fangyong Li, Martina Wade, Jonathan French, Liusheng Huang, Francesca Aweeka, Norah Mwebaza, Richard Kajubi, Matthew Riggs, Ana Ruiz-Garcia, Sunil Parikh. Clin Pharmacol Ther. Published online October 19, 2022. doi:10.1002/cpt.2768

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

Impact of drug exposure on resistance selection following artemether-lumefantrine treatment for malaria in children with and without HIV in Uganda

Katherine Kay, Justin Goodwin, Hanna Ehrlich, Joyce Ou, Tracey Freeman, Kaicheng Wang, Fangyong Li, Martina Wade, Jonathan French, Liusheng Huang, Francesca Aweeka, Norah Mwebaza, Richard Kajubi, Matthew Riggs, Ana Ruiz-Garcia, Sunil Parikh. Clin Pharmacol Ther. Published online October 19, 2022. doi:10.1111/cpt.2768

Extrapolation of Efficacy of a Dextroamphetamine Transdermal System from Pediatric to Adult Populations Using Pharmacokinetic Modeling.

Mariacristina Castelli, Katsumi Suzuki, Brittney Starling, Kanan Balakrishnan, Suzanne Meeves, Marina Komaroff, Janelle Lennie, John T. Mondick, Stephen V. Faraone.
Presented at the American Society of Clinical Psychopharmacology Annual Meeting, May 31–June 3, 2022, in Scottsdale, AZ. Poster #W2

A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis: Assessment of Target Attainment with Extended-Interval Dosing through Simulation

Kevin J. Downes, Austyn Grim, Laura Shanley, Ronald C. Rubenstein, Athena F. Zuppa, Marc R. Gastonguay. Antimicrob Agents Chemother. 2022;66(5):e0237721.

Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children

Aruldhas BW, Quinney SK, Overholser BR, Heathman MA, Masters AR, Ly RC, Gao H, Packiasabapathy S, Sadhasivam S. CPT Pharmacometrics Syst Pharmacol2021001– 12. doi:10.1002/psp4.12687

Population pharmacokinetic and exposure–efficacy analysis of ixekizumab in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS)

Jackson K, Chua L, Velez de Mendizabal N, Pitou C, Rodriguez Capriles C, Paller AS, Lansang P, Seyger M, Papp K, IXORA-PEDS study group. Br J Clin Pharmacol20211– 13. doi:10.1111/bcp.15034

Pharmacometric Dose Optimization of Buprenorphine in Neonatal Opioid Withdrawal Syndrome

Eudy-Byrne R, Zane N, Adeniyi-Jones SC, Gastonguay MR, Ruiz-Garcia A, Kushal G, Kraft WK. Clin Transl Sci. 2021;14:2171-2183. doi:10.1111/cts.13074

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.

Modeling and simulation of lumefantrine pharmacokinetics in HIV-infected and HIV-uninfected children with malaria and the role of lumefantrine exposure as a potential driver of drug resistance

Kay K, Goodwin J, Mwebaza N, Ruiz A, Ehrlich H, Ou J, Freeman T, Wade M, Huang L, Wang K, Li F, Aweeka FT, Riggs M, Kajubi R, Parikh S.  Presented at the annual meeting of the American Society of Tropical Medicine and Hygiene, October 16-18, 2020.

The use of exposure-response with therapeutic proteins in pediatric drug development

Presentation by Marc Gastonguay, Ph.D., at the 2020 Virtual Annual Meeting of the American College of Clinical Pharmacology (ACCP) during the symposium: Innovative Approaches in the Use of Exposure-Response in Therapeutic Proteins to Support Pediatric Extrapolation. 23 September 2020.

Simplified models to assess gestational age in low-middle income countries: Findings from the multi-site AMANHI study

A.C. Lee, K.E. Semrau, B. Wylie, A.H. Baqui, B. Kirkwood, A.A. Manu, F. Jehan, M. Nisar, S. Sazawal, U. Dhingra, D.H. Hamer, J.D. Wilbur, S. Yoshida, R. Bahl.  Simplified Models to Assess Gestational Age in Low-Middle Income Countries: Findings from the Multi-site AMANHI Study.  Pediatric Academic Societies Meeting, May 2, 2020. E-PAS2020:1555.6

The use of modeling & simulation to facilitate an understanding of pediatric dose-exposure-response for small molecules and biologics

Presented by Marc Gastonguay, Ph.D. at the DIA Pediatric Drug Development Workshop on October 28, 2019. Event details on the DIA website.

Leveraging Multiple R Tools to Make Effective Pediatric Dosing Decisions

Fisher, Jeannine. Presentation at R/Pharma. Cambridge, MA. 22 Aug 2019.

The use of R in the development of physiological model for healthy growth

Eudy-Byrne R. Lightning Talk presented at the 1st annual R/Pharma conference. Boston, MA. 15 August 2018.

A model of the effects of GI disease and diet on child body composition in order to improve outcomes in those suffering from malnutrition

Eudy-Byrne R. Presented at the 17th American Pediatrics Healthcare & Infectious Diseases Congress, Vancouver, Canada, 28 June 2018.

Population PK modeling and target attainment simulations to support dosing of ceftaroline fosamil in pediatric patients with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia

Riccobene TA, Khariton T, Knebel W, Das S, Li J, Jandourek A, Carrothers TJ, Bradley JS.  The Journal of Clinical Pharmacology, March 2017; 57: 345–355. doi: 10.1002/jcph.809

Population pharmacokinetic and pharmacodynamic analysis of buprenorphine for the treatment of neonatal abstinence syndrome

Moore JN, Gastonguay M, Adeniyi-Jones S, Moodey DE, Kraft WK.  Poster presented at: American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting, March 2017, Washington, DC; Abstract PII-099.

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.

Dexmedetomidine pharmacology in neonates and infants after open heart surgery

Su F, Gastonguay MR, Nicolson SC, DiLiberto M, Ocampo-Pelland A, Zuppa AF. Anesth Analg. 2016 May;122(5):1556-66.

Population pharmacokinetic modeling of guanfacine in pediatric patients

Knebel W, Corcoran M, Ermer J, Gastonguay MR.  Clinical Pharmacokinetics (2015) 54: 875. doi:10.1007/s40262-015-0245-7

Modeling and simulation of the exposure-response and dropout pattern of guanfacine extended-release in pediatric patients with ADHD

Knebel W, Rogers JA, Polhamus D, Ermer J, Gastonguay MR. Journal of Pharmacokinetics and Pharmacodynamics, Feb 2015, Volume 42, Issue 1, pp 45–65. doi:10.1007/s10928-014-9397-6

Methods for determining similarity of exposures between adult and pediatric patients and trial design considerations

Marc Gastonguay. Presented at CERSI Workshop on the Use of Exposure Matching and Exposure Response for Extrapolation of Efficacy in Pediatric Drug Development. January 22, 2015.

Population pharmacokinetics of ε-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery

Stricker PA, Gastonguay MR, Singh D, Fiadjoe JE, Sussman EM, Pruitt EY, Goebel TK, and Zuppa AF.  BJA: British Journal of Anaesthesia, 114(4), 689–699.

Population pharmacokinetic (PPK) modeling and simulation to support pediatric dose selection of ceftaroline fosamil (CPT-F) in children aged 28 days to 12 years

Khariton T, Riccobene T, Knebel W, O’Neal T, Ghahramani P. Presented at the 5th American Conference on Pharmacometrics (ACoP), Las Vegas, NV, October 2014.

Population pharmacokinetic/pharmacodynamic modeling of guanfacine effects on QTc and heart rate in pediatric patients

W. Knebel, J. Ermer, J. Purkayastha, P. Martin, and M. R. Gastonguay.  The AAPS Journal. 2014;16(6):1237-1246. doi:10.1208/s12248-014-9645-0.

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery

Stricker PA, Zuppa AF, Fiadjoe JE, Maxwell LG, Sussman EM, Pruitt EY, Goebel. TK, Gastonguay MR, Taylor JA, Bartlett SP, Schreiner MS.  Br J Anaesth. 2013 May;110(5):788-99. doi: 10.1093/bja/aes507

Population pharmacokinetics of atorvastatin and its active metabolites in children and adolescents with heterozygous familial hypercholesterolemia: Selective use of informative prior distributions from adults

Knebel W, Gastonguay MR, Malhotra B, El-Tahtawy A, Jen F and Gandelman K.  J Clin Pharmacol. 2013 May; 53 (5): 505-16. doi: 10.1002/jcph.66.

Modeling and simulation of guanfacine extended-release to support pediatric trial design

Knebel W, Rogers JA, Polhamus D, Youcha S, White C, Ermer J, and Gastonguay M. American Academy of Child and Adolescent Psychiatry, 59th Annual Meeting. 2012.

Population pharmacokinetics of pentobarbital in neonates, infants, and children after open heart surgery

Zuppa AF, Nicolson SC, Barrett JS, Gastonguay MR.  J Pediatr. 159(3):414-419.e1-3. September 2011.