Extrapolation of Adult Efficacy to Pediatric Patients With Chemotherapy‐Induced Nausea and Vomiting

Momper, Jeremiah D.; Heinrichs, M. Tobias; Krudys, Kevin; Griebel, Donna; Kumar, Shaun S.; Kim, Insook; Mehrotra, Nitin; Mulberg, Andrew E.; Garimella, Narayana; Nelson, Robert M.; Reaman, Gregory H.; Sinha, Vikram; Yao, Lynne; Zineh, Issam; Burckart, Gilbert J.; Sachs, Hari Cheryl; Mulugeta, Yeruk

doi:10.1002/jcph.1577

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…Statistical and computational innovations in drug development have the potential to further advance the use of pediatric extrapolation. [24][25][26][27] One such innovation is modeling and simulation, which has been used to generate pharmacokinetic information for several of the drugs in this analysis, including abatacept, ceftazidime-avibactam, daptomycin, entrectinib, and insulin degludec. [28][29][30][31][32] Other innovative approaches such as the use of bridging biomarkers and Bayesian methodologies have been used to support pediatric extrapolation.…”

Section: Discussionmentioning

confidence: 99%

Pediatric Efficacy Extrapolation in Drug Development Submitted to the US Food and Drug Administration 2015–2020

Samuels

Park

Bhatt‐Mehta

et al. 2022

The Journal of Clinical Pharma

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Pediatric extrapolation plays a key role in the availability of reliable pediatric use information in approved drug labeling. This review examined the use of pediatric extrapolation in studies submitted to the US Food and Drug Administration and assessed changes in extrapolation approaches over time. Pediatric studies of 125 drugs submitted to the US Food and Drug Administration that led to subsequent pediatric information in drug labeling between 2015 and 2020 were reviewed. The use of pediatric extrapolation for each drug was identified and categorized as "complete," "partial," or "no" extrapolation. Approaches to pediatric extrapolation of efficacy changed over time. Complete extrapolation of efficacy was the predominantly used approach. "Complete," "partial," or "no" extrapolation was used for 51%, 23%, and 26% of the drugs, respectively. This represents a shift in extrapolation approaches when compared to a previous study that evaluated pediatrics drug applications between 2009 and 2014, which found complete, partial, or no extrapolation was used for 34%, 29%, and 37% of the drugs, respectively. Pediatric extrapolation approaches may continue to shift as emerging science fills gap in knowledge of the fundamental assumptions underlying this scientific tool. The international community continues to collaborate on discussions of pediatric extrapolation of efficacy from adults and other pediatric subpopulations to optimize its use for pediatric drug development.

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Section: Discussionmentioning

confidence: 99%

Pediatric Efficacy Extrapolation in Drug Development Submitted to the US Food and Drug Administration 2015–2020

Samuels

Park

Bhatt‐Mehta

et al. 2022

The Journal of Clinical Pharma

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“…This remains a critical research gap. Although not ideal, established adult drug doses can be scaled for administration to children 46 . Scaled doses are usually then administered to children in a research setting to determine a dose that achieves the pharmacokinetic profile associated with safe and effective use in adults.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone dosing for prevention of acute chemotherapy‐induced vomiting in pediatric patients: A systematic review

Patel

Olteanu

Cabral

et al. 2020

Pediatric Blood & Cancer

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A systematic review was undertaken to describe dexamethasone doses studied for chemotherapy-induced vomiting (CIV) prophylaxis in pediatric patients and their effects on achieving complete acute CIV control. No dose-finding studies were identified. However, 16 studies assessing pediatric patients who received dexamethasone were included and classified according to the emetogenicity of chemotherapy administered. Eight different total daily dexamethasone doses were administered to patients on day 1 of highly emetogenic chemotherapy: three in conjunction with aprepitant/fosaprepitant plus a 5HT 3 antagonist and five in conjunction with a 5HT 3 antagonist. Five different total daily dexamethasone doses were administered in conjunction with a 5HT 3 antagonist to patients on day 1 of moderately emetogenic chemotherapy. Due to the heterogeneity of studies identified, meta-analysis was not possible. The optimal dexamethasone dose to control acute CIV and to minimize harms in pediatric patients remains uncertain. This is a key area for future research. K E Y W O R D S chemotherapy-induced nausea and vomiting, dexamethasone, pediatric oncology, supportive care 1 INTRODUCTION Chemotherapy-induced nausea and vomiting (CINV) are two of the most distressing side effects of chemotherapy. 1-3 They have a negative influence on quality of life, have been associated with decreased growth in children, and can lead to patients becoming nonadherent with oral chemotherapy and refusing to continue cancer treatment. 4-6 Dexamethasone has been included in pediatric CINV prophylaxis regimens for over three decades. 7 Current clinical practice guidelines (CPGs) for the prevention of acute CINV strongly recommend that pediatric patients receive dexamethasone in combination with Abbreviations: CINV, chemotherapy-induced nausea and vomiting; CIV, chemotherapy-induced vomiting; CPG, clinical practice guideline; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy aprepitant and a 5HT 3 antagonist during receipt of highly emetogenic chemotherapy (HEC) or in combination with a 5HT 3 antagonist during receipt of moderately emetogenic chemotherapy (MEC). 8-11 These CPGs acknowledge that there are circumstances when clinicians may wish to avoid the use of dexamethasone as an antiemetic and recommend alternatives. Such circumstances include brain tumors where corticosteroids may prevent chemotherapy distribution into the central nervous system 12 ; acute myelogenous leukemia where corticosteroids may further increase the already high risk of fungal infection 12 ; and use of chemotherapy where efficacy is compromised by concurrent corticosteroid use. 11 Nevertheless, inclusion of dexamethasone in pediatric CINV prophylaxis regimens and its appropriate dose are hotly debated among the pediatric oncology community. For example, two of 36 Children's Oncology Group member institutions responding to a survey in 2015 never administered dexamethasone for CIV

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“…The chemotherapy protocols in children are often intensive and multi-day, unlike adult protocols, which are largely single-day. Yet, pediatric guidelines and dosing strategies for anti-emetic prophylaxis are largely derived by extrapolation from studies conducted in adults [6]. There is a need for clinicians to better understand the pharmacology of anti-emetics in children to facilitate CINV control by optimizing the dosing strategies in this population.…”

Section: Introductionmentioning

confidence: 99%

Anti-Emetics in Children Receiving Chemotherapy for Solid Tumors and Leukemia: Pharmacology and Optimization of Therapy for Nausea and Vomiting

Ganguly,

Sasi,

Nagaraju

et al. 2024

Pharmaceuticals

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The management of chemotherapy-induced nausea and vomiting (CINV) in children remains challenging due to differences in the chemotherapy regimens, their relative emetogenicity compared to that in adults and differences in drug metabolism and the available formulations. The common four classes of anti-emetics used for the treatment and prophylaxis of CINV in children include dexamethasone, neurokinin-1 receptor antagonists, 5-hydroxytryptamine-3 receptor antagonists (5HT3RAs), and olanzapine. The appropriate dose of dexamethasone for CINV prophylaxis in children is unknown, with a significant variability in dosage ranging between 6 and 32 mg/m2/day. The dose of dexamethasone is decreased by 30% when this drug is combined with (fos)aprepitant in children, in contrast to a decrease of 50% required in adults. The use of aprepitant in younger children (<12 years) is often hampered by the non-availability of oral suspension formulations in many countries; alternatively, 80 mg capsules are administered for 1–3 days in certain institutes to children weighing between 15 and 40 kg. Among the different 5HT3RAs, palonosetron is comparatively metabolized faster in children than in adults, requiring a higher dosage for similar efficacy to that achieved in adults. Olanzapine is a newer agent, used in doses between 0.1 and 0.14 mg/kg/day in children, with good anti-emetic efficacy, but has sedation and hyperglycemia as concerning adverse effects. Drug interactions between anti-emetics and between anti-emetics and chemotherapy/supportive agents (azole antifungals, cyclosporine, arsenic trioxide), especially QTc prolongation, should be considered during prescription.

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Extrapolation of Adult Efficacy to Pediatric Patients With Chemotherapy‐Induced Nausea and Vomiting

Cited by 5 publications

References 15 publications

Pediatric Efficacy Extrapolation in Drug Development Submitted to the US Food and Drug Administration 2015–2020

Pediatric Efficacy Extrapolation in Drug Development Submitted to the US Food and Drug Administration 2015–2020

Dexamethasone dosing for prevention of acute chemotherapy‐induced vomiting in pediatric patients: A systematic review

Anti-Emetics in Children Receiving Chemotherapy for Solid Tumors and Leukemia: Pharmacology and Optimization of Therapy for Nausea and Vomiting

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