Abstract: Chemotherapy-induced nausea and vomiting (CINV) is a common treatment-related adverse event that negatively impacts the quality of life of cancer patients. During pediatric drug development, extrapolation of efficacy from adult to pediatric populations is a pathway that can minimize the exposure of children to unnecessary clinical trials, improve efficiency, and increase the likelihood of success in obtaining a pediatric indication. The acceptability of the use of extrapolation depends on a series of evidence-based assumptions regarding the similarity of disease, response to intervention, and exposure-response relationships between adult and pediatric patients. This study evaluated publicly available summaries of data submitted to the US Food and Drug Administration for drugs approved for CINV to assess the feasibility of extrapolation for future development programs. Extracted data included trial design, emetogenic potential of chemotherapy, primary end points, participant enrollment criteria, and antiemetic pharmacokinetics. Adult and pediatric clinical trial designs for assessment of efficacy and safety shared key design elements. Antiemetic drugs found to be efficacious in adults were also efficacious in pediatric patients. Systemic drug concentrations at approved doses were similar for ondansetron, granisetron, and aprepitant, but an exposure-response analysis of palonosetron in children suggested that higher palonosetron systemic exposure is necessary for the prevention of CINV in the pediatric population. For 5-hydroxytryptamine-3 and neurokinin-1 receptor antagonist antiemetic drugs, efficacy in adults predicts efficacy in children, supporting the extrapolation of effectiveness of an antiemetic product in children from adequate and well-controlled studies in adult patients with CINV.
(© 2020, The American College of Clinical Pharmacology.)
References: Miller M, Kearney N. Chemotherapy-related nausea and vomiting-past reflections, present practice and future management. Eur J Cancer Care. 2004;13:71-81.
Navari RM, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;374:1356-1367.
Jordan K, Jahn F, Aapro M. Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review. Ann Oncol. 2015;26:1081-1090.
Field MJ, Boat TF, eds. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: National Academy of Sciences; 2012.
Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128:e1242-1249.
Ollivier C, Mulugeta YL, Ruggieri L, Saint-Raymond A, Yao L. Paediatric extrapolation: a necessary paradigm shift. Br J Clin Pharmacol. 2019;85:675-679.
Addendum to ICH E11: clinical investigation of medicinal products in the pediatric population E11(R1). International Conference of Harmonisation. 2017. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/E11-R1EWG_Step4_Addendum_2017_0818.pdf Accessed October 21, 2019.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products. March 2019.
Rothmond DA, Weickert CS, Webster MJ. Developmental changes in human dopamine neurotransmission: cortical receptors and terminators. BMC Neurosci. 2012;13:18.
Engel M, Smidt MP, van Hooft JA. The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front Cellular Neurosci. 2013;7:76.
Wu C, Dias P, Kumar S, Lauder JM, Singh S. Differential expression of serotonin 5-HT2 receptors during rat embryogenesis. Dev Neurosci. 1999;21:22-28.
Taoka M, Song SY, Kubota M, Minegishi A, Yamakuni T, Konishi S. Increased level of neurokinin-1 tachykinin receptor gene expression during early postnatal development of rat brain. Neuroscience. 1996;74:845-853.
Del Cadia M, De Rienzo F, Weston DA, Thompson AJ, Menziani MC, Lummis SC. Exploring a potential palonosetron allosteric binding site in the 5-HT(3) receptor. Bioorg Med Chem. 2013;21:7523-7528.
Rojas C, Stathis M, Thomas AG, et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg. 2008;107:469-478.
Freedman JL, Faerber J, Kang TI, et al. Predictors of antiemetic alteration in pediatric acute myeloid leukemia. Pediatr Blood Cancer. 2014;61:1798-1805.
Holdsworth MT, Raisch DW, Frost J. Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer. 2006;106:931-940.
Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006;5:27-36. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM605696.pdf. Accessed September 4, 2019.
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