Methodological and Ethical Issues in Pediatric Medication Safety Research

Carpenter, Delesha M.; González, Daniel; Retsch‐Bogart, George; Sleath, Betsy; Wilfond, Benjamin S.

doi:10.1542/peds.2017-0195

Cited by 13 publications

(9 citation statements)

References 43 publications

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“…A closer inspection reveals that most PGx research on SSA populations involves single gene–drug relationships; however, multigene–drug or gene panel testing provides a higher predictability of individual drug response. In addition, most studies have excluded pediatric populations, which is probably due to the existence of specific pediatric pharmacovigilance tools, including age-dependent drug dosage, relying on child-reported ADRs and the engagement of children and child care-givers in the research process [ 49 ]. The absence of clinical studies evaluating the economic value of implementing PGx testing in SSA health-care systems is also noteworthy, given that government and private insurers require evidence of the cost–utility of clinical tests for reimbursements.…”

Section: Paucity Of Clinical Pharmacogenetics Studies In Ssamentioning

confidence: 99%

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

Tata

Ambele

2020

Pharmaceutics

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Clinical research in high-income countries is increasingly demonstrating the cost- effectiveness of clinical pharmacogenetic (PGx) testing in reducing the incidence of adverse drug reactions and improving overall patient care. Medications are prescribed based on an individual’s genotype (pharmacogenes), which underlies a specific phenotypic drug response. The advent of cost-effective high-throughput genotyping techniques coupled with the existence of Clinical Pharmacogenetics Implementation Consortium (CPIC) dosing guidelines for pharmacogenetic “actionable variants” have increased the clinical applicability of PGx testing. The implementation of clinical PGx testing in sub-Saharan African (SSA) countries can significantly improve health care delivery, considering the high incidence of communicable diseases, the increasing incidence of non-communicable diseases, and the high degree of genetic diversity in these populations. However, the implementation of PGx testing has been sluggish in SSA, prompting this review, the aim of which is to document the existing barriers. These include under-resourced clinical care logistics, a paucity of pharmacogenetics clinical trials, scientific and technical barriers to genotyping pharmacogene variants, and socio-cultural as well as ethical issues regarding health-care stakeholders, among other barriers. Investing in large-scale SSA PGx research and governance, establishing biobanks/bio-databases coupled with clinical electronic health systems, and encouraging the uptake of PGx knowledge by health-care stakeholders, will ensure the successful implementation of pharmacogenetically guided treatment in SSA.

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Section: Paucity Of Clinical Pharmacogenetics Studies In Ssamentioning

confidence: 99%

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

Tata

Ambele

2020

Pharmaceutics

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“…Also, the propensity for pharmacokinetic differences between children and adults is well known. Pediatric medication safety research faces the difficulty of assessing child-reported adverse drug events ( 298 ).…”

Section: Considerations In Designing Future Clinical Trials For Neuromentioning

confidence: 99%

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

Pranzatelli

2018

Front. Immunol.

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The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic). Human cerebrospinal fluid (CSF) studies have been instrumental in revealing soluble immunobiomarkers involved in immune dysregulation, their dichotomous effects, and the cells—often subtype specific—that produce them. CKs/cytokines continue to be attractive targets for the pharmaceutical industry with varying therapeutic success. This review summarizes the developing armamentarium, complexities of not compromising surveillance/physiologic functions, and insights on applicable strategies for neuroinflammatory disorders. The main approach has been using a designer monoclonal antibody to bind directly to the chemo/cytokine. Another approach is soluble receptors to bind the chemo/cytokine molecule (receptor ligand). Recombinant fusion proteins combine a key component of the receptor with IgG1. An additional approach is small molecule antagonists (protein therapeutics, binding proteins, and protein antagonists). CK neutralizing molecules (“neutraligands”) that are not receptor antagonists, high-affinity neuroligands (“decoy molecules”), as well as neutralizing “nanobodies” (single-domain camelid antibody fragment) are being developed. Simultaneous, more precise targeting of more than one cytokine is possible using bispecific agents (fusion antibodies). It is also possible to inhibit part of a signaling cascade to spare protective cytokine effects. “Fusokines” (fusion of two cytokines or a cytokine and CK) allow greater synergistic bioactivity than individual cytokines. Another promising approach is experimental targeting of the NLRP3 inflammasome, amply expressed in the CNS and a key contributor to neuroinflammation. Serendipitous discovery is not to be discounted. Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.

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“…The physiological differences in pediatrics have not been fully characterized, which has made identifying safe and effective doses in this population a challenge 1 . In addition, the vulnerable nature of this population leads to limited sample size, and ethical barriers prevent pediatric research from being carried out 1,2 . As a result of lacking pediatric data, many medications are used off‐label in children with limited information on the optimal use 3 .…”

Section: Case Studymentioning

confidence: 99%

Understanding the Role of Pharmacometrics‐Based Clinical Decision Support Systems in Pediatric Patient Management: A Case Study Using Lyv Software

Jarugula

Ivaturi

Noack

et al. 2021

The Journal of Clinical Pharma

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Pharmacometrics could play a key role in shifting pediatric pharmacotherapy from dosing for an average patient to individualizing dosing. Clinicians can have these quantitative tools at their disposal without requiring significant training through the development of clinical decision support systems with easy‐to‐use interfaces that have a back‐end analysis engine or pharmacometric model that uses extensive electronic health record data to predict an individualized dose for each patient. There has been increased development of these clinical decision support systems recently, and for these tools to make the proper breakthrough into clinical practice, it is of utmost importance to perform rigorous testing to ensure adequate predictive performance. In this article, we walk through the components of a decision support tool and the testing required to determine its robustness using an example of a decision support tool we developed for vancomycin dosing in pediatrics.

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Methodological and Ethical Issues in Pediatric Medication Safety Research

Cited by 13 publications

References 43 publications

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

Understanding the Role of Pharmacometrics‐Based Clinical Decision Support Systems in Pediatric Patient Management: A Case Study Using Lyv Software

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