Pediatric Extrapolation in Type 2 Diabetes: Future Implications of a Workshop

Barrett, Jeffrey S.; Bucci‐Rechtweg, Christina; Cheung, S.Y. Amy; Gamalo, Margaret; Haertter, Sebastian; Karres, Janina; Marquard, Jan; Mulugeta, Yeruk; Ollivier, Cécile; Strougo, Ashley; Yanoff, Lisa B.; Yao, Lynne; Zeitler, Philip

doi:10.1002/cpt.1805

Cited by 11 publications

(14 citation statements)

References 31 publications

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“…Within this database, we identified a cohort of children and adolescents aged 10‐18 years. This age range is consistent with the US Food and Drug Administration (FDA) and the European Medicines Agency's recommendations for studying the development of drugs for T2D in paediatric patients 2 …”

Section: Methodssupporting

confidence: 83%

“…approval of new agents). The newer antidiabetic agents have been increasingly used in adults, particularly as second‐line treatment for T2D, 37,38 and there has been a growing interest in the development of new antidiabetic agents in paediatric patients 2 . Liraglutide is the only new agent with a paediatric indication, and while its use remained low, there was a sharp increase in use in late 2019 after paediatric approval was granted.…”

Section: Discussionmentioning

confidence: 99%

“…obesity, prediabetes). Paediatric trials evaluating the efficacy and safety of new non‐insulin antidiabetic medications are ongoing, 2,3 and in June 2019, liraglutide (a glucagon‐like peptide‐1 receptor agonist [GLP‐1 RA]) was the first non‐insulin antidiabetic medication to receive paediatric approval since metformin in 2000 4…”

Section: Introductionmentioning

confidence: 99%

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Antidiabetic medication use in commercially insured children and adolescents in the United States from 2004 to 2019

Sun

Hernández–Dı́az

Bourgeois

et al. 2020

Diabetes Obesity Metabolism

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Aim To describe the patterns of non‐insulin antidiabetic medication use, initiation and adherence in the paediatric population. Methods We conducted a descriptive study of non‐insulin antidiabetic medication use in children and adolescents (aged 10‐18 years) using real‐world data from a nationwide US commercial claims database (January 2004–September 2019). Trends in the prevalence of non‐insulin antidiabetic medication use overall and by class were evaluated. Among new users of non‐insulin antidiabetic agents, medication adherence was examined using group‐based trajectory models. Results In a cohort of more than 1 million paediatric patients, the prevalence of any non‐insulin antidiabetic medication use was 75.7 per 100 000 patients in 2004 and more than doubled to 162.0 per 100 000 in 2019. Biguanides (metformin) was by far the most widely used medication class. The use of newer classes was low (<10 per 100 000), but there was an uptake in the use of glucagon‐like peptide‐1 receptor agonists after liraglutide received paediatric approval in 2019. Medication adherence was poor during the 18 months after treatment initiation: 79.6% of initiators experienced an early treatment interruption (median time to interruption: 90 days among metformin monotherapy initiators) and 21% of initiators did not return for a prescription refill after the first month. Conclusions There was a substantial increase in non‐insulin antidiabetic medication use among commercially insured paediatric patients from 2004 to 2019. Nearly all patients were treated with metformin, while the use of newer agents remained low. Despite the increase in medication use, short treatment episodes were observed, even among patients with a diagnosis of type 2 diabetes, raising concern over poor adherence.

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Section: Methodssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Antidiabetic medication use in commercially insured children and adolescents in the United States from 2004 to 2019

Sun

Hernández–Dı́az

Bourgeois

et al. 2020

Diabetes Obesity Metabolism

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“…PBPK modeling can offer advantages over a simpler population PK model if there are patient‐specific and/or disease‐specific physiologic characteristics that may affect drug PK and/or PD. If there are known PD, efficacy, and safety differences that can be reliably and quantitatively expressed in a model, then a PK/PD‐linked model (using PBPK or population PK) or a quantitative systems pharmacology model may be applied as suggested in previous publications 26,27 …”

Section: Discussionmentioning

confidence: 99%

Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study

Zhu

Willmann

Zhou

et al. 2022

The Journal of Clinical Pharma

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Thrombosis remains an important complication for children with single-ventricle physiology following the Fontan procedure, and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose-finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined using a model-informed drug development approach. A physiologically based pharmacokinetic rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults. This regimen was used in an open-label, multicenter phase III study, which investigated the use of rivaroxaban for thromboprophylaxis in post-Fontan patients 2 to 8 years of age. The pharmacokinetics (PK) of rivaroxaban was assessed in part A (n = 12) and in part B (n = 64) of the UNIVERSE study. The safety and efficacy in the rivaroxaban group were compared to those in the acetylsalicylic acid group for 12 months. Pharmacodynamic end points were assessed in both parts of the study. Rivaroxaban exposures achieved in parts A and B were similar to the adult reference exposures. Prothrombin time also showed similarity to the adult reference.Exposure-response analysis did not identify a quantitative relationship between rivaroxaban exposures and efficacy/safety outcomes within the observed exposure ranges. A body weight-based dose regimen selected by physiologically based pharmacokinetic modeling was shown in the UNIVERSE study to be appropriate for thromboprophylaxis in the post-Fontan pediatric population. Model-based dose selection can support pediatric drug development and bridge adult dose data to pediatrics, thereby obviating the need for dose-finding studies in pediatric programs.

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“…Augmenting the placebo arm of a clinical trial with historical controls from prior trials or from well-curated and matched realworld cohorts also holds the potential to decrease the overall size of trials and limit exposure to placebo in those trials while potentially increasing power to detect efficacy signals [47,48]. In addition, should we find, as we come to better understand youth-onset T2D, that the response to therapies is sufficiently similar to that in adults, sponsors may be able to extrapolate from adult data based on pharmacokinetic and pharmacologic data from adolescents with T2D [49]. Future use of such innovative approaches will require careful consultation and coordination between industry sponsors and regulators.…”

Section: Discussionmentioning

confidence: 99%

A Review of Interventional Trials in Youth-Onset Type 2 Diabetes: Challenges and Opportunities

et al. 2021

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Introduction: In recent decades, the dramatic rise of obesity among youth in the US has been accompanied by a rise in the prevalence of type 2 diabetes (T2D) in this population. This alarming trend underscores the importance of conducting trials to evaluate new therapies in children with T2D. Methods: A targeted review of peer-reviewed literature and trials registered on www. clinicaltrials.gov was conducted in January 2021 to identify pharmaceutical interventional studies in youth with T2D. Information regarding enrollment data, study design elements, subjects' baseline characteristics, and key treatment outcomes was documented. Results: Among the 16 clinical studies included in this review, only five appeared to meet projected enrollment targets in \ 4 years. Although three other studies met recruitment targets, two took approximately 5 years to complete and the third took nearly 10 years. Conclusions: Despite legislation requiring evaluation of pharmaceutical treatments in pediatric populations, surprisingly few interventional studies have been conducted in children with T2D. This review highlights that recruitment challenges may be impeding the conduct and completion of interventional studies. Consequently, few pharmaceutical treatments have been proven to be effective and approved for children with T2D. Metformin and liraglutide remain the only non-insulin treatments formally approved in the US for use in this population. More clinical research is needed to support regulatory decision-making as well as treatment decisions for children with T2D in clinical settings. Sponsors and investigators will need to implement strategies for improving trial enrollment as well as work with regulatory agencies to develop novel study designs that may require fewer patients.

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Pediatric Extrapolation in Type 2 Diabetes: Future Implications of a Workshop

Cited by 11 publications

References 31 publications

Antidiabetic medication use in commercially insured children and adolescents in the United States from 2004 to 2019

Antidiabetic medication use in commercially insured children and adolescents in the United States from 2004 to 2019

Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study

A Review of Interventional Trials in Youth-Onset Type 2 Diabetes: Challenges and Opportunities

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