title: Bridging strategies for drug combinations in pediatric indications.
abstract: Concurrent prescription of different drugs is common and is often necessary in many pediatric indications. A randomized concentration-controlled trial (RCCT) is proposed for pediatric studies in which drug combinations are used. The aim of our investigation was to show the relevance of flexible designs for accurate dose selection in such cases. We used the combination of atovaquone (ATV) and proguanil (PGN) as a paradigm to illustrate our approach. Pharmacokinetic models were developed for ATV and PGN using data pertaining to adults. The median area under the curve (AUC) in adults was considered the target exposure for bridging purposes. A pediatric population was simulated according to scenarios in which clearance varied from 20 to 100% of the reference adult values or allometrically correlated with body weight (BW). Doses were subsequently adapted according to the individual AUC estimates. Our results show that adaptive protocols are critical for accurate dose selection when evaluating drug combinations in children, ensuring that target exposure is achieved with respect to both active moieties in each individual patient.
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Cella
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: O
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000293:Adolescent; D000367:Age Factors; D053626:Atovaquone / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D002727:Proguanil / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012042:Registries
chemical_list: D004338:Drug Combinations; D002727:Proguanil; D053626:Atovaquone