Role of exposure-response analysis to guide dose selection in pediatric drug development when extrapolating efficacy from adults

Abstract

Purpose: Efficacy in pediatrics can be extrapolated from adequate and well controlledadult trials if it is reasonable to assume that disease progression andresponse to intervention in pediatrics is similar to adults. The knowledge of pharmacokinetics(PK) and exposure‐response (ER) plays an important role in dose selection.If it is reasonable to assume similar ER relationships between pediatrics and adults, then a pediatric dose is selected to achieve exposures similar to adult therapeuticdose. However, if this assumption cannot be made, then ER relationship can be usedto select doses in children. The purpose of this communication is to highlight howPK, ER and clinical data are used to select doses in children using the example ofinfliximab treatment of ulcerative colitis (UC). This topic was discussed at the FDAGastrointestinal Drugs Advisory Committee meeting on July 21, 2011.PROJECT DESCRIPTION: An open‐label, randomized, parallel‐group study was conductedto assess safety and efficacy of infliximab induction and maintenancetreatment in 60 patients aged 6 through 17 years with moderately to severelyactive UC despite adequate conventional therapy. The induction regimen was 5mg/kg i.v. administered at weeks 0, 2, and 6. Responders at week 8 wererandomized to 5 mg/kg q8 or q12 week dosing regimen (maintenance treatment)with an option to increase the dose or dosing frequency in case of loss ofresponse. FDA conducted post‐hoc ER analyses to examine whether the dosingregimen is appropriate. Logistic regression analyses of infliximab serum concentrationand clinical response (week 8) or remission (week 54) were conducted. Asimilar analysis was also performed using data from adult UC clinical trials. Results: During the induction phase, ER was similar in pediatrics and adults.Approximately 70% of children and adults had clinical response at week 8 with concentration >20 lg/mL. Because ER was similar, the pediatric dose is based onobtaining similar infliximab exposures. Following 5 mg/kg induction dose, medianserum concentrations in pediatrics (29 lg/mL) were similar to adults (33 lg/mL).Limited data in the maintenance phase precluded the evaluation of ER; therefore, pediatric dose selection depended on PK and clinical data. Steady‐state troughlevels in pediatrics (1.9 lg/mL) were slightly lower than adults (2.5 lg/mL). However, based on adult ER relationship, slightly lower exposures do not appear toresult in lower response in pediatrics. Furthermore, the remission rate at week 54in adults (35%) and pediatrics (38%) after 5 mg/kg q8 dose was also similar. Insummary, similar PK and ER in pediatrics and adults supported the 5 mg/kginduction dose. Although, ER was not demonstrated in pediatrics in the maintenancephase, PK and clinical observations supported the maintenance dose. Conclusions: Extrapolation of efficacy in pediatrics from adults increasesefficiency of pediatric drug development by maximizing use of adult data andavoids unnecessary pediatric trials. PK and ER analysis have a critical role in dose selection. The knowledge gained about PK and drug effects in adults should beleveraged to guide pediatric drug development to expedite access to safe andeffective medicines for pediatrics.