During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the U.S. Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the two patient populations. The main measures were the pediatric PK studies trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmax and AUC ratios (pediatric/adult) of 0.63-4.19 and 0.36-3.60 respectively. Seven of the 86 trials (8.1%) had a pre-defined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.

Keywords: pediatrics, drug development, dosing, exposure matching, extrapolation
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Introduction
Extrapolation of efficacy findings from adults to the pediatric population is an approach that was first proposed by the U.S. Food and Drug Administration (FDA) in the 1994 Pediatric Labeling Rule to maximize the use of adult and other data when designing pediatric drug development programs. The Rule was supplanted by the Best Pharmaceuticals Children's Act (BPCA) in 2002 and Pediatric Research Equity Act (PREA) in 2003. These requirements and incentives were made permanent as of 2012 with the passing of the FDA Safety and Innovation Act (FDASIA). The extrapolation concept was reflected in Regulations under 21 CFR 314.55 and has been further described in a pediatric study planning algorithm published by the FDA.1

Extrapolation of efficacy from adults to pediatric patients relies on the assumptions that the course of the disease and the response to the investigational drug are sufficiently similar between the adult and intended pediatric population. Based on the sufficiency of the data in support of these assumptions, extrapolation of efficacy from adequate, well-controlled studies with adults to the pediatric population can be categorized as either full extrapolation or partial extrapolation. In either circumstance, a pharmacokinetic (PK) study in the relevant age group may be conducted to determine dosing in the pediatric population. In 2011, the experience of the FDA in interpreting the use of extrapolation of efficacy in pediatric drug development programs was reviewed.2 Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as full for 14.5% of the products (24 of 166) and partial for 68% (113 of 166). When extrapolation was used, a larger percentage (61%) of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group, but this number decreased to 34% (10 of 29) when there was no extrapolation.

A key component for both partial and full extrapolation is selecting dosing regimens that achieve pediatric exposures “similar” to adults.1 A dosing regimen must be identified that results in an exposure range or distribution comparable to what has been observed in the reference population, most often adults. However, currently guidance is lacking about the best methods for matching adult systemic exposures in pediatric studies. The objective of this study was to examine prior approaches to exposure matching and exposure agreement for adult and pediatric patients as the basis for pediatric dose selection for trials submitted to the FDA under BPCA from 1998 to 2012 and PREA from 2007 to 2012.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482171/

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Definitions and Outcomes
We used area under the curve from time zero to infinity (AUC0-∞) or zero to a given time point (AUC0-t) available in drug submissions to determine exposure matching between children and adults. We preferentially extracted median values if available for both children and adults, followed by geometric mean, and then arithmetic mean.

For individual drugs, we described exposure matching between children and adults by the following criteria: 1 median (or mean) pediatric AUC within 20% of the reported adult value; 2) median (or mean) pediatric AUC within 50% of the reported adult value; or 3) ≥75% of pediatric AUC ranges within the reported adult range. Pediatric exposure was defined as “within 20% of the median (or mean) adult exposure” if the ratio of the pediatric to adult AUC was 0.8 to 1.2 for all age groups in which sponsors were seeking approval.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039072/

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Note added at 1 hr (2023-01-25 09:52:46 GMT)
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Ik kom niet verder dan:

exposure matching between children and adults -->

de blootstelling bij kinderen in overeenstemming brengen met die bij volwassenen

of

de dosering bij kinderen in overeenstemming brengen met die bij volwassenen

adult exposure matching -->

de blootstelling/dosering in overeenstemming brengen met die bij volwassenen

exposure agreement --> overeenkomt in blootstelling / dosering