Model‐Informed Drug Development in Pediatric Dose Selection

Bi, Youwei; Liu, Jiang; Li, Fang; Yu, Jingyu; Bhattaram, Atul; Bewernitz, Michael; Li, Ruo‐Jing; Ahn, Ji-Hye; Earp, Justin; Ma, Lian; Zhuang, Luning; Yang, Yuching; Zhang, Xinyuan; Zhu, Hao; Wang, Yaning

doi:10.1002/jcph.1848

Cited by 11 publications

(24 citation statements)

References 42 publications

(59 reference statements)

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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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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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“…In conclusion, P-PBPK models are being increasingly used as part of MIDD, and the case studies presented illustrate that integrating and leveraging existing knowledge 35 allows a more mechanistic approach to inform dose selection (e.g., small and large molecules) and formulation bridging and extrapolate DDIs. Despite the recognized potential of P-PBPK modeling, the approach still appears to lag behind other approaches, such as POP-PK in pediatric drug development.…”

Section: Conclusion/discussionmentioning

confidence: 98%

Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations

Johnson

Small

Yeo

2022

CPT Pharmacom & Syst Pharma

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There has been a significant increase in the use of physiologically based pharmacokinetic (PBPK) models during the past 20 years, especially for pediatrics.The aim of this study was to give a detailed overview of the growth and areas of application of pediatric PBPK (P-PBPK) models. A total of 181 publications and publicly available regulatory reviews were identified and categorized according to year, author affiliation, platform, and primary application of the P-PBPK model (in clinical settings, drug development or to advance pediatric model development in general). Secondary application areas, including dose selection, biologics, and drug interactions, were also assessed. The growth rate for P-PBPK modeling increased 33-fold between 2005 and 2020; this was mainly attributed to growth in clinical and drug development applications. For primary applications, 50% of articles were classified under clinical, 18% under drug development, and 33% under model development. The most common secondary applications were dose selection (75% drug development), pharmacokinetic prediction and covariate identification (47% clinical), and model parameter identification (68% model development), respectively. Although population PK modeling remains the mainstay of approaches supporting pediatric drug development, the data presented here demonstrate the widespread application of P-PBPK models in both drug development and clinical settings. Although applications for pharmacokinetic and drug-drug interaction predictions in pediatrics is advocated, this approach remains underused in areas such as assessment of pediatric formulations, toxicology, and trial design. The increasing number of publications supporting the development and refinement of the pediatric model parameters can only serve to enhance optimal use of P-PBPK models.

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“…It has application throughout drug development as it is included in at least 25 guidance documents, 16 but is particularly important for rare diseases because of the challenges of the small number of patients and limited observations. 17 There are a wide variety of models that are used throughout drug development.…”

Section: Model-informed Drug Development (Midd)mentioning

confidence: 99%

“…Model‐informed drug development (MIDD), also known as model‐informed drug discovery and development (MID3), 15 is the development and application of models to integrate observations, fill in gaps, and improve decisions, making drug development more efficient. It has application throughout drug development as it is included in at least 25 guidance documents, 16 but is particularly important for rare diseases because of the challenges of the small number of patients and limited observations 17 . There are a wide variety of models that are used throughout drug development.…”

Section: Regulatory Programs and Regulatory Science Innovation For Al...mentioning

confidence: 99%

Regulatory Framework for Drug Development in Rare Diseases

Korth‐Bradley

2022

The Journal of Clinical Pharma

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Drug development is a highly regulated industry. Therapeutic options for rare diseases must meet the same high standards for the demonstration of safety and efficacy as do those for more common diseases. The approval of the Orphan Drug Act in 1983 has resulted in many more resources for preclinical research, the standardization of patient registries, and the use of real‐world data, among other measures, that, along with the advances in drug development, has resulted in the approval of therapies for some of the most unusual diseases. Increased attention to the diagnosis and treatment of rare diseases has also accelerated the development of gene therapies that may offer significant amelioration and even cures for such diseases in the near future. Rare diseases disproportionately affect children, with severe and debilitating effects. Few effective treatments are available for most rare diseases. To avoid the unnecessary waste of data collected in studies of these patients, and to promote efficient drug development, there is a growing collaboration among patient communities, investigators, clinicians, sponsors, and regulatory authorities. All interested parties are working together to identify the most appropriate research questions and move quickly to make available safe and effective treatments. This article is a survey of the most commonly used regulatory remedies that have been put in place to serve as a framework for drug development in rare diseases.

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Model‐Informed Drug Development in Pediatric Dose Selection

Cited by 11 publications

References 42 publications

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

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

Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations

Regulatory Framework for Drug Development in Rare Diseases

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