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Bridging Strategies for Drug Combinations in Pediatric Indications
Author(s) -
Cella M,
Danhof M,
Della Pasqua O
Publication year - 2012
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.298
Subject(s) - bridging (networking) , medicine , drug , pharmacokinetics , population , area under the curve , pharmacology , computer science , computer network , environmental health
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. Clinical Pharmacology & Therapeutics (2012); 91 4, 726–733. doi: 10.1038/clpt.2011.298