Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development

Population pharmacokinetics (PK) and exposure‐response (E‐R) analyses were conducted to compare the PK and E‐R relationships of golimumab between children and adults with ulcerative colitis. PK data following subcutaneous golimumab administration to children with ulcerative colitis (6‐17 years) in the PURSUIT‐PEDS‐PK study, adults with ulcerative colitis in the PURSUIT study, and children with pediatric polyarticular juvenile idiopathic arthritis (2‐17 years) in the GO‐KIDS study, were included in the population PK analysis. E‐R analysis was conducted using logistic regression to link serum golimumab concentration and Mayo score–based efficacy outcomes in pediatric and adult ulcerative colitis. Golimumab PK was adequately described by a 1‐compartment model with first‐order absorption and elimination. Golimumab apparent clearance and volume of distribution increased with body weight. Golimumab apparent clearance was higher in patients with lower serum albumin, no methotrexate use, and positive antibodies to golimumab; age was not an influential factor after accounting for body weight. Model‐estimated terminal half‐life (9.2 days in children; 9.5 days in adults) and other PK parameters suggest that golimumab PK properties are generally comparable between children and adults with ulcerative colitis. Simulations suggest that a higher induction dose than that tested in PURSUIT‐PEDS‐PK may be needed for children ≤45 kg to achieve exposures comparable to adults. Comparable E‐R relationships between children and adults with ulcerative colitis were observed, although children appeared to be more responsive for the more stringent remission end point. The overall comparable PK and E‐R relationships between children and adults support the extrapolation of golimumab efficacy from the adult to the pediatric ulcerative colitis population.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Population Pharmacokinetics and Exposure‐Response Modeling Analyses of Golimumab in Children With Moderately to Severely Active Ulcerative Colitis

Adedokun

Chan

et al. 2018

“…However, exposure matching has been found to be ineffective in many cases, leading to clinical trial failures in pediatrics. Inconsistency of exposure‐matching techniques contributes to this ineffectiveness . However, variability in PD is not addressed by exposure matching and is much greater than variability in PK .…”

Section: Quantitative Information May Be Obtained From Trials In Adulmentioning

confidence: 99%

“…Extrapolation of efficacy from studies in adults and older children to pediatric and neonatal populations can maximize the use of available data and minimize the exposure of children to unnecessary clinical trials . According to the FDA extrapolation scheme, pediatric and adult PK data are matched to quantify exposure agreement between the patient populations in full extrapolation .…”

Section: Quantitative Information May Be Obtained From Trials In Adulmentioning

confidence: 99%

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

Conklin

Hoffman

Anker

2019

Challenges in pediatric drug development include small patient numbers, limited outcomes research, ethical barriers, and sparse biosamples. Increasingly, pediatric drug development is focusing on extrapolation: leveraging knowledge about adult disease and drug responses to inform projections of drug and clinical trial performance in pediatric subpopulations. Pharmacokinetic‐pharmacodynamic (PK‐PD) modeling and extrapolation aim to reduce the numbers of patients and data points needed to establish efficacy. Planning for PK‐PD and biomarker studies should begin early in the adult drug development program. Extrapolation relies on the assumption that both the underlying disease and the mechanism of action of the drug used to treat that disease are similar in adults and pediatric subpopulations. Clearly, developmental changes in PK and PD need to be considered to enhance the quality of PK‐PD modeling and, therefore, increase the success of extrapolation. This article focuses on the influence of differences in PD between adults and pediatric subpopulations that are highly relevant for the use of extrapolation.

“…20 If dose selection is based on PK and/or PD data, the study should be prospectively powered based on adult data to achieve precise estimates of relevant PK and/or PD parameters with consideration of the feasibility. If dose selection is based on toxicity or demonstration of efficacy, adequate PK and/or PD data should be collected.…”

Section: Extrapolation Of Pediatric Efficacy From Adult Studiesmentioning

confidence: 99%

Bridging Adult Experience to Pediatrics in Oncology Drug Development

Leong

Zhao

Reaman

et al. 2017

Pediatric drug development in the United States has grown under the current regulations made permanent by the Food and Drug Administration Safety and Innovation Act of 2012. Over 1200 pediatric studies have now been submitted to the US FDA, but there is still a high rate of failure to obtain pediatric labeling for the indication pursued. Pediatric oncology represents special problems in that the disease is most often dissimilar to any cancer found in the adult population. Therefore, the development of drug dosing in pediatric oncology patients represents a special challenge. Potential approaches to pediatric dosing in oncology patients include extrapolation of efficacy from adult studies in those few cases where the disease is similar, inclusion of adolescent patients in adult trials when possible, and bridging the adult dose to the pediatric dose. An analysis of the recommended phase 2 dose for 40 molecularly targeted agents in pediatric patients provides some insight into current practices. Increased knowledge of tumor biology and efforts to identify and validate molecular targets and genetic abnormalities that drive childhood cancers can lead to increased opportunities for precision medicine in the treatment of pediatric cancers.