Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development

Abstract

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 US 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 2 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 C_max and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined 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: dosing; drug development; exposure matching; extrapolation; pediatrics.

Figure 1

Distribution of products reviewed (1998-2012).

Figure 2

Ratios (pediatric/adult) for Products Approved at the Studied Dose. The solid line corresponds to a ratio of one. The 90% confidence intervals are based on the Fieller's method.

Figure 3

Forest Plot of Cmax and AUC Ratios (pediatric/adult) for Products without a Pediatric Indication. The solid line corresponds to a ratio of one. The 90% confidence intervals are based on the Fieller's method

Figure 4

Forest Plot of Cmax and AUC Ratios (pediatric/adult) for Products Approved with a Different Dose. The solid line corresponds to a ratio of one. The 90% confidence intervals are based on the Fieller's method.

Figure 5

Bland-Altman Plot of Cmax Pediatric/Adult Ratios and AUC Pediatric/Adult Ratios. Bland and Altman Plot of the data obtained from 90 age groups with Cmax pediatric/adult ratios and AUC pediatric/adult ratios; Correlation R = 0.85 (P<0.001). The blue line corresponds to the mean difference of the two ratios; the lower and the upper red lines correspond to the lower and the upper 95% confidence limits for the mean difference.