Use of Modeling and Simulation in the Design and Conduct of Pediatric Clinical Trials and the Optimization of Individualized Dosing Regimens

Barrett, Jeffrey S.; Roberts, Jessica K.; Sherwin, Catherine M.T.

doi:10.1002/psp4.12038

Cited by 28 publications

(23 citation statements)

References 54 publications

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“…Specifically, in this manuscript, we focus on the latter aspect to illustrate how pharmacometric principles were used to make regulatory decisions related to pediatric approval and labeling. Discussions around utilizing pharmacometric approaches to design informative clinical trials in pediatrics can be found elsewhere (Jadhav and Kern, 2010;Stockmann et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Advances in the science of quantitative pharmacology and the use of model-based drug development have paralleled the advances in pediatric research (Stockmann et al, 2015;Vinks et al, 2015). The use of modeling and simulation (M&S) as an integral part of and basis for improving efficiency, substantiating trial design, and optimizing dose selection in pediatric drug development has been communicated in recent guidance (http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ucm425885.pdf).…”

Section: Introductionmentioning

confidence: 99%

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Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Mehrotra¹,

Bhattaram²,

Earp³

et al. 2016

Drug Metabolism and Disposition

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Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twicedaily regimen, different once-daily dosing regimens for treatmentnaïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Mehrotra¹,

Bhattaram²,

Earp³

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…In particular, an ongoing application of the ASMD QSP model is to support the extrapolation of olipudase alfa to the pediatric population. Modeling and simulation is becoming an increasingly important tool in pediatric drug development, and has been encouraged by regulatory agencies . In particular, the key role of mechanistic modeling approaches (e.g., QSP) as a complement to empirical approaches (e.g., PK/PD modeling) during pediatric extrapolation has been recognized and recommended .…”

Section: Discussionmentioning

confidence: 99%

“…Modeling and simulation is becoming an increasingly important tool in pediatric drug development, and has been encouraged by regulatory agencies. [36][37][38][39][40] In particular, the key role of mechanistic modeling approaches (e.g., QSP) as a complement to empirical approaches (e.g., PK/PD modeling) during pediatric extrapolation has been recognized and recommended. 41 QSP provides a unique and useful mechanism-based perspective for evaluating disease and response similarity and the potential factors affecting progression and intervention response in pediatrics compared with adult patients.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology

Kaddi

Niesner

Baek

et al. 2018

CPT Pharmacom & Syst Pharma

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Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non‐neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular‐level, cellular‐level, and organ‐level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient‐specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics.

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“…Simulations can increase the likelihood of trial success by deriving optimal dosing for phase III studies and precise estimates of power, sample size, and the effects of dropout [57, 58]. The models can also test hypotheses relevant to trial design- for example, the effect of age stratification on outcome.…”

Section: Future Directionsmentioning

confidence: 99%

Clinical Trial Design in Juvenile Idiopathic Arthritis

et al. 2017

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Randomized clinical trials provide the gold standard evidence base to guide clinical practice. Despite major advances in trial design, pediatric clinical trials are still difficult to perform and pose unique challenges, including the need to consider the impact of developmental changes in trial design. Advances within pediatric rheumatology combined with the need to comply with legislative requirements have driven new approaches to performing pediatric clinical trials such as utilization of large research networks, incorporation of patient and family stakeholders in the planning and implementation of clinical trials, and the development of novel trial designs. The expansion of available biological therapeutics that now includes biosimilar drugs highlights the important and difficult balance of providing new and cost effective drugs to children while ensuring safety in a vulnerable population. Future advances in JIA clinical trials will likely be the application of precision medicine based on biologic, rather than phenotypic, classification of JIA, with improved understanding of pediatric clinical pharmacology. Clinical trial simulations and comparative effectiveness studies are important supplements to traditional clinical trials, permitting efficient studies and results that are more generalizable.

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Use of Modeling and Simulation in the Design and Conduct of Pediatric Clinical Trials and the Optimization of Individualized Dosing Regimens

Cited by 28 publications

References 54 publications

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology

Clinical Trial Design in Juvenile Idiopathic Arthritis

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