Exposure–Response Assessment in Pediatric Drug Development Studies Submitted to the US Food and Drug Administration

Zhang, Yifei; Wang, Yaning; Khurana, Mona; Sachs, Hari Cheryl; Zhu, Hao; Burckart, Gilbert J.; Alexander, John J.; Yao, Lynne; Wang, Jian

doi:10.1002/cpt.1809

Cited by 14 publications

(15 citation statements)

References 10 publications

(10 reference statements)

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“…Model‐informed drug development (MIDD) will continue to play a larger part in pediatric drug development and drug dosing. Our results reinforce that popPK is used in >90% of programs involving MIDD, but the more complex approaches have now been described as applications of exposure‐response 32 and physiologically based PK 33 . Multiple examples now exist as to how MIDD can put together complex information in a pediatric drug development program to predict dosing and ultimately affect drug labeling 34 …”

Section: Discussionsupporting

confidence: 71%

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

Green

Park

Burckart

2021

The Journal of Clinical Pharma

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Dosing is a critical aspect of drug development in pediatrics that has led to trial failures and the inability to label the drug for pediatric use by the US Food and Drug Administration. Developing a structured approach for pediatric dose selection requires knowledge of the current approaches and their success or failure. This study describes the current experience with pediatric dosing methods from 2012 to 2020 and had 2 primary objectives: (1) to identify how the initial pediatric dose was selected and (2) to identify the pivotal dosing strategy used to identify the initially selected dose for safety and efficacy for pediatric clinical trials. Through September 2020, a total of 275 pediatric drug development programs were characterized for initial and pivotal dosing strategies. The success rate for labeling for pediatric use was 76.4%. The most common initial dosing strategy was previous experience with the product, followed by allometric scaling and exposure matching with adults. The most common pivotal dosing strategy was titration to target response in 33% of programs, with the second and third most common being pharmacokinetic/pharmacodynamic studies (30%) and exposure matching (20%), respectively. Additionally, about one‐half of pediatric programs incorporated model‐informed drug development. The emergence of titration to target response may signal a shift toward precision medicine in pediatric patients. Future work in pediatric drug dose selection should move toward the development of a structured pediatric dose selection approach.

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Section: Discussionsupporting

confidence: 71%

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

Green

Park

Burckart

2021

The Journal of Clinical Pharma

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“…32,37 This may require the incorporation of more innovative and quantitative approaches to improve the robustness of the analysis. 38,39 In addition to efficacy extrapolation, we would also like to advocate for pediatric PK extrapolation to potentially replace or minimize pediatric phase I studies, an area which has been gaining credence since 2015. 18,40 The issues can be highlighted by our earlier trials, such as the phase I pediatric study investigating pregabalin, which took ~ 5 years to complete, and more specifically, the 1 month to < 2 years age group, for which it took > 2 years to recruit sufficient patients.…”

Section: Future Perspectivesmentioning

confidence: 99%

Pregabalin Population Pharmacokinetic and Exposure‐Response Analyses for Focal Onset Seizures in Children (4–16 years) and Adults, to Support Dose Recommendations in Children

Chan

Marshall

McFadyen

et al. 2021

Clin Pharma and Therapeutics

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Pregabalin is approved in multiple countries as adjunctive therapy for adult patients with focal onset seizures (FOS; previously termed partial onset seizures). This study used population pharmacokinetic (PK) and exposure–response (E‐R) analyses from pooled pregabalin concentration and efficacy data to compare pregabalin exposure and E‐R relationships in pediatric and adult patients with FOS, to support pediatric dosage recommendations. A one‐compartment disposition model was used, with first‐order absorption and body surface area‐normalized creatinine clearance on clearance. Individual pregabalin average steady‐state concentrations were predicted and used in an E‐R analysis of efficacy. The E‐R relationship of pregabalin was similar in pediatric (4–16 years) and adult patients with FOS after accounting for differences in baseline natural log‐transformed 28‐day seizure rate and placebo effect. Population PK simulations showed that children aged 4–16 years and weighing ≥ 30 kg required pregabalin 2.5–10 mg/kg/day to achieve similar pregabalin exposure at steady‐state to adult patients receiving the approved doses of 150–600 mg/day. For children 4–16 years weighing < 30 kg, a higher pregabalin dose of 3.5–14 mg/kg/day was required to achieve equivalent exposure at steady‐state. The results support the dosage guidance provided in the pregabalin prescribing label, whereby pediatric patients (4–16 years) weighing < 30 kg should receive a 40% higher pregabalin dose (per kg of body weight) than patients weighing ≥ 30 kg to achieve similar exposure. Our combined modeling approach may provide guidance for future extrapolation assessment from adult to pediatric patients.

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“…This approach allowed us to characterize the population pharmacokinetics of lacosamide in young pediatric patients suffering from epilepsy who receive lacosamide therapy in an off-label environment and to derive potential dosing recommendations in this understudied age group. The applied exposure matching approach has extensively been used by the FDA and others to facilitate extrapolation of adult clinical pharmacology data to pediatric populations [22][23][24][25] and is supported by the recent findings of the Pediatric Epilepsy Academic Consortium for Extrapolation. 6 The pharmacokinetics of lacosamide in pediatric patients >1 month of age could adequately be described by weight-based allometric modeling without the need for any further age-associated maturation function.…”

Section: Discussionmentioning

confidence: 99%

Use of Real‐World Data and Pharmacometric Modeling in Support of Lacosamide Dosing in Pediatric Patients Under 4 Years of Age

Lukka

Woods

Chhim

et al. 2021

The Journal of Clinical Pharma

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The antiepileptic drug lacosamide (LCM) is approved in the United States and the European Union as monotherapy as well as adjunctive therapy for the treatment of focal seizures in children ≥4 years of age and adults. Using real‐world therapeutic drug monitoring data, we performed a pharmacometric analysis for 315 pediatric patients (>1 month to <18 years of age) who received lacosamide as both monotherapy and adjunctive therapy. Population pharmacokinetic modeling was performed using nonlinear mixed‐effects modeling with a 1‐compartment structural model with linear elimination, where clearance and volume of distribution were allometrically scaled for body weight, with no further need for age‐associated maturation functions. A covariate analysis for age, sex, race, and coadministration of other antiepileptic drugs identified phenobarbital and felbamate to significantly increase lacosamide clearance (1.71‐ and 1.46‐fold, respectively). Based on the developed population pharmacokinetic model, simulations were performed in virtual pediatric patients to explore age‐associated dose requirements to match lacosamide exposure in patient groups of different age with the exposure achieved in children ≥4 year of age with the weight‐based dosing recommendations provided by the US Food and Drug Administration. Based on this approach, our analysis suggested that children ≥3 years of age needed the same dose as recommended by the US Food and Drug Administration for children ≥4 years of age (12 mg/kg/d), while children 1 to 3 years of age may need 13 to 14 mg/kg/d and infants between 1 month and 1 year of age may need 15 to 18 mg/kg/d (based on their actual age) to match the exposure seen in children ≥4 years of age.

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Exposure–Response Assessment in Pediatric Drug Development Studies Submitted to the US Food and Drug Administration

Cited by 14 publications

References 10 publications

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

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

Pregabalin Population Pharmacokinetic and Exposure‐Response Analyses for Focal Onset Seizures in Children (4–16 years) and Adults, to Support Dose Recommendations in Children

Use of Real‐World Data and Pharmacometric Modeling in Support of Lacosamide Dosing in Pediatric Patients Under 4 Years of Age

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