Methods Used for Pediatric Dose Selection in Drug Development Programs Submitted to the US FDA 2012‐2020

Green, Francis G.; Park, Kyunghun; Burckart, Gilbert J.

doi:10.1002/jcph.1853

Cited by 10 publications

(23 citation statements)

References 35 publications

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“…Balancing simplicity and generalizability, the focus was on keeping the tables as simple as possible. The use of allometric and other scaling methods as alternative to PBPK methods through these tables may reduce resources required to select the initial dose for first-in-child trials and can be used as a structured approach to pediatric dose selection [41]. Additionally, these scaling methods can be used to optimize informative sampling times based on the scaled clearance [42,43].…”

Section: Discussionmentioning

confidence: 99%

An Update on the Use of Allometric and Other Scaling Methods to Scale Drug Clearance in Children: Towards Decision Tables

Rongen

Krekels

Calvier

et al. 2022

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: When pediatric data are not available for a drug, allometric and other methods are applied to scale drug clearance across the pediatric age-range from adult values. This is applied when designing first-in-child studies, but also for off-label drug prescription. Areas covered: This review provides an overview of the systematic accuracy of allometric and other pediatric clearance scaling methods compared to gold-standard PBPK predictions. The findings are summarized in decision tables to provide a priori guidance on the selection of appropriate pediatric clearance scaling methods for both novel drugs for which no pediatric data are available and existing drugs in clinical practice. Expert opinion: While allometric scaling principles are commonly used to scale pediatric clearance, there is no universal allometric exponent (i.e. 1, 0.75, or 0.67) that can accurately scale clearance for all drugs from adults to children of all ages. Therefore, pediatric scaling decision tables based on age, drug elimination route, binding plasma protein, fraction unbound, extraction ratio, and/or isoenzyme maturation are proposed to a priori select the appropriate (allometric) clearance scaling method, thereby reducing the need for full PBPK-based clearance predictions. Guidance on allometric scaling when estimating pediatric clearance values is provided as well.

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Section: Discussionmentioning

confidence: 99%

An Update on the Use of Allometric and Other Scaling Methods to Scale Drug Clearance in Children: Towards Decision Tables

Rongen

Krekels

Calvier

et al. 2022

Expert Opinion on Drug Metabolism & Toxicology

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“…Nevertheless, the TMDD model described herein provides insights into myostatin coverage in pediatric patients with DMD as compared with healthy adult volunteers. Ensuring that the appropriate dosing rationale and regimen are used in pediatric clinical trials, as well as identifying potential patient subgroups who may be more sensitive to treatment (in terms of efficacy and safety), remains a challenge in pediatric drug development 18,19 . It is therefore essential to accurately characterize the underlying PK/PD relationships, especially in children as these are likely to change as they age.…”

Section: Discussionmentioning

confidence: 99%

Population PK and PD Analysis of Domagrozumab in Pediatric Patients with Duchenne Muscular Dystrophy

Wojciechowski

Purohit

Harnisch³

et al. 2022

Clin Pharma and Therapeutics

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Myostatin, a negative regulator of skeletal muscle growth, is a therapeutic target in muscle‐wasting diseases. Domagrozumab, a humanized recombinant monoclonal antibody, binds myostatin and inhibits activity. Domagrozumab was investigated in a phase II trial (NCT02310763) as a potential treatment for boys with Duchenne muscular dystrophy (DMD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling is vital in clinical trial design, particularly for determining dosing regimens in pediatric populations. This analysis sought to establish the PK/PD relationship between free domagrozumab and total myostatin concentrations in pediatric patients with DMD using a prior semimechanistic model developed from a phase I study in healthy adult volunteers (NCT01616277) and following inclusion of phase II data. The refined model was developed using a multiple‐step approach comprising structural, random effects, and covariate model development; assessment of model adequacy (goodness‐of‐fit); and predictive performance. Differences in PKs/PDs between healthy adult volunteers and pediatric patients with DMD were quantitatively accounted for and evaluated by predicting myostatin coverage (the percentage of myostatin bound by domagrozumab). The final model parameter estimates and semimechanistic target‐mediated drug disposition structure sufficiently described both domagrozumab and myostatin concentrations in pediatric patients with DMD, and most population parameters were comparable with the prior model (in healthy adult volunteers). Predicted myostatin coverage for phase II patients with DMD was consistently > 90%. Baseline serum myostatin was ~ 65% lower than in healthy adult volunteers. This study provides insights into the regulation of myostatin in healthy adults and pediatric patients with DMD. http://clinicaltrials.gov identifiers: NCT01616277 and NCT02310763.

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“…Various dosing methods may be used to determine pediatric drug dosages, including weight-based and allometric scaling. [21][22][23] However, determining the optimal dosages for use in pediatric patients who are obese is complicated, and may require dedicated studies in patients who are obese. 6,21,24,25 In 1 systematic review of the literature, drug exposure levels in children who were obese, compared with controls who were not obese, was evaluated.…”

Section: Discussionmentioning

confidence: 99%

Obesity Considerations in Pediatric Drug Development, 2016–2021

Samuels,

Bhatt‐Mehta,

Park

et al. 2023

The Journal of Clinical Pharma

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Pediatric obesity is a global public health concern. Obesity‐related physiological changes may affect the pharmacokinetics of drugs and lead to therapeutic failure or toxicities. An earlier review of pediatric drug development programs from 2007 to 2016 found that, of 89 programs listing obesity‐related terms, only 4 (4%) products described pharmacokinetic changes associated with obesity. This review examined obesity considerations for 185 drug products for which pediatric drug development programs were submitted to the US Food and Drug Administration (FDA) between 2016 and 2021. The FDA‐authored review documents and drug product labeling were queried for obesity‐related terms and the review found 97/185 (52%) drug products had obesity‐related terms in these sources. Of the 97 drug products, 55/97 (57%) had obesity‐related terms in the FDA‐authored reviews only, 13/97 (13%) had obesity‐related terms in the drug product labeling only, and 29/97 (30%) had obesity‐related terms in both FDA‐authored reviews and drug product labeling. Most of the obesity‐related information in the drug product labeling originated from data collected from adults. Only 13/185 (7%) drug product labeling contained obesity‐related terms in reference to drug pharmacokinetics. Specific dosage recommendations for the use of the drug products in pediatric patients who are obese remain lacking. The dearth of available information to guide drug dosages in the obese pediatric population suggests that further research, innovative approaches, and evidence‐based guidelines are needed to inform the optimal therapeutic use of drugs in this population.

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Methods Used for Pediatric Dose Selection in Drug Development Programs Submitted to the US FDA 2012‐2020

Cited by 10 publications

References 35 publications

An Update on the Use of Allometric and Other Scaling Methods to Scale Drug Clearance in Children: Towards Decision Tables

An Update on the Use of Allometric and Other Scaling Methods to Scale Drug Clearance in Children: Towards Decision Tables

Population PK and PD Analysis of Domagrozumab in Pediatric Patients with Duchenne Muscular Dystrophy

Obesity Considerations in Pediatric Drug Development, 2016–2021

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