Extrapolation of Efficacy and Dose Selection in Pediatrics: A Case Example of Atypical Antipsychotics in Adolescents With Schizophrenia and Bipolar I Disorder

Kalaria, Shamir N.; Farchione, Tiffany; Uppoor, Ramana; Mehta, Mehul; Wang, Yaning; Zhu, Hao

doi:10.1002/jcph.1836

Cited by 8 publications

(23 citation statements)

References 23 publications

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“…Although complete extrapolation of efficacy was not used for any psychiatry drugs in this review, the treatment of schizophrenia and bipolar I disorder during adolescence has received much attention. An analysis of clinical trials evaluating atypical antipsychotic drugs that share a similar mechanism of action indicated similarities in symptomatic changes, response to treatment, drug exposures, and exposure–response relationship between adults and pediatric patients with manic/mixed episodes associated with bipolar I disorder and schizophrenia 23 . With such advancement in understanding, this is an area of therapeutics that may qualify for pediatric extrapolation in the future.…”

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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“…2. To support full extrapolation of efficacy from adults to pediatric patients Attention deficiency and hyperactive disorder (30) To support back extrapolation of efficacy from children to adolescents and adults for CNS stimulant products Schizophrenia and bipolar I disorder (31) To support full extrapolation of efficacy from adults to pediatric patients Oncology (32) To support the use of the modeling and simulation-based pharmacokinetic criteria for the approval of an alternative dosing regimen of programmed death 1 (PD-1) and programmed death ligand 1 (PD L-1) antibodies…”

Section: Role Of Midd Approaches In Addressing Biopharmaceutics Issuesmentioning

confidence: 99%

Review: Role of Model-Informed Drug Development Approaches in the Lifecycle of Drug Development and Regulatory Decision-Making

et al. 2022

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Model-informed drug development (MIDD) is a powerful approach to support drug development and regulatory review. There is a rich history of MIDD applications at the U.S. Food and Drug Administration (FDA). MIDD applications span across the life cycle of the development of new drugs, generics, and biologic products. In new drug development, MIDD approaches are often applied to inform clinical trial design including dose selection/optimization, aid in the evaluation of critical regulatory review questions such as evidence of effectiveness, and development of policy. In the biopharmaceutics space, we see a trend for increasing role of computational modeling to inform formulation development and help strategize future in vivo studies or lifecycle plans in the post approval setting. As more information and knowledge becomes available pre-approval, quantitative mathematical models are becoming indispensable in supporting generic drug development and approval including complex generic drug products and are expected to help reduce overall time and cost. While the application of MIDD to inform the development of cell and gene therapy products is at an early stage, the potential for future application of MIDD include understanding and quantitative evaluation of information related to biological activity/pharmacodynamics, cell expansion/ persistence, transgene expression, immune response, safety, and efficacy. With exciting innovations on the horizon, broader adoption of MIDD is poised to revolutionize drug development for greater patient and societal benefit. KEY WORDS biopharmaceutics • generic drugs • gene therapy • model-informed drug development • new drugs * Rajanikanth Madabushi

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“…Computational modeling of PK data can guide dose selection, helping to minimize the risk of unnecessary overexposure and increased side effects in the vulnerable pediatric patient population. Prior work using this approach with other antipsychotics has highlighted the utility of extrapolating efficacy from adult to pediatric patients 14 . For example, physiologically based pharmacokinetic modeling on data from adult patient populations was successfully used to predict the PK of an extended‐release formulation of quetiapine for use in pediatric and adolescent populations 15 .…”

mentioning

confidence: 99%

“…Prior work using this approach with other antipsychotics has highlighted the utility of extrapolating efficacy from adult to pediatric patients. 14 For example, physiologically based pharmacokinetic modeling on data from adult patient populations was successfully used to predict the PK of an extended-release formulation of quetiapine for use in pediatric and adolescent populations. 15 Similarly, a mixed-effects population PK model developed with adult data was adjusted for body size using allometric scaling to treat pediatric populations with loxapine.…”

mentioning

confidence: 99%

Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin

Darwish

Bugarski‐Kirola²,

Jaworowicz

et al. 2023

The Journal of Clinical Pharma

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Pimavanserin is a selective serotonin‐modulating agent with inverse agonist/antagonist activity at the 5‐HT2A receptor. Safety and efficacy of pimavanserin 34 mg once daily was studied in adults with hallucinations and delusions associated with Parkinson's disease psychosis and other neuropsychiatric conditions. This analysis used model‐based simulations of pimavanserin steady‐state exposures to identify a dose that generated pediatric exposures comparable with adult exposures achieved with 34 mg pimavanserin.A population pharmacokinetics model was developed using pooled plasma drug concentration (i.e., actual) data from 13 clinical studies, including a phase 1 study of adolescent pediatric patients (13‐17 years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (i.e., simulated) group of pediatric patients (5‐17 years). Steady‐state measures of area under the plasma concentration‐time curve (AUC) and maximum drug concentration (Cmax) were simulated for relevant age and weight stratifications and compared with simulated exposures in adults (18‐49 years).Simulated mean AUC ranged 47.41‐54.73 ng·d/mL and mean Cmax ranged 41.13‐50.07 ng/mL in adults receiving pimavanserin 34 mg. Simulated mean (SD) Cmax with 34 mg pimavanserin was similar in patients aged 10–17 years (56.54 [24.58] ng/mL) and adults. Pimavanserin 20 mg yielded a mean (SD) Cmax most like the 34‐mg adult Cmax in patients aged 5–9 years (45.30 [21.31] ng/mL) and in the 14–25 kg pediatric patient weight group (49.18 [22.91] ng/mL).Pimavanserin 20 and 34 mg in pediatric patients aged 5–9 and 10–17 years, respectively, yielded exposures similar to daily pimavanserin 34 mg in adults aged 18–49 years.This article is protected by copyright. All rights reserved

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Extrapolation of Efficacy and Dose Selection in Pediatrics: A Case Example of Atypical Antipsychotics in Adolescents With Schizophrenia and Bipolar I Disorder

Cited by 8 publications

References 23 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

Review: Role of Model-Informed Drug Development Approaches in the Lifecycle of Drug Development and Regulatory Decision-Making

Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin

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