Febuxostat Pharmacokinetic/Pharmacodynamic Bridging From Adults To Pediatrics For Effective Prophylaxis Of Tumor Lysis Syndrome: From Florence To Floret Study

Background Febuxostat, a potent and selective xanthine oxidase inhibitor, showed a significantly superior serum uric acid (sUA) control during chemotherapy (CT) in comparison to Allopurinol (Spina M. et al, ASCO 2014 and Annals of Oncology in press) when given as 120 mg oral fixed daily dosed and has been recently approved in the European Union (EU) for the prevention and treatment of hyperuricemia in adult patients undergoing CT for hematologic malignancies (HM) at intermediate- high Tumor Lysis Syndrome (TLS) risk, with recognition of the high relevance of its clinical benefit. Some pediatric HM are highly prone to develop TLS; an age-appropriate drug formulation for TLS prophylaxis is lacking in this population, resulting in an unmet medical need that Febuxostat is going to address. The similarities between adult and pediatric patients in terms of TLS pathogenesis, clinical manifestations and current management allow using pharmacokinetic (PK) information to extrapolate clinical efficacy and safety from adult to pediatric patients, as well as within the different pediatric ages (EMEA/CHMP/EWP/147013/2004). Methods A phase I/II study (Floret) has been designed to explore the PK/pharmacodynamic (PK/PD) profile of Febuxostat in the pediatric population in comparison to adults. Febuxostat daily dose will be 120 mg for adolescents and adults with a lower 80 mg dose to be administered to adolescents only, to obtain confirmatory data on the optimal exposure in terms of safety and effectiveness compared to adults. Considering the difference in body size and organ maturation, the selected daily doses of Febuxostat to be tested in children aged 6 to 11 years are 40 and 60 mg. As the only approved strengths of Febuxostat in the EU are 80 and 120 mg, an age-appropriate 20 mg tablet formulation of Febuxostat is developed to ensure the adequate dosing in children. In accordance to the European Medicines Agency Guidelines CHMP/EWP/147013/2004 and CHMP/EWP/18599/2006, the choice of population PK analysis, using non-linear mixed effect models, is considered appropriate to obtain the necessary precision of PK parameters estimates for the comparability assessment between the groups of patients. The PD/efficacy measurement, namely the sUA area under curve from baseline to the evaluation visit, corresponding to the primary efficacy measure explored during the Florence study, a Phase III comparative trial in adults vs Allopurinol (Spina M et al, ASCO 2014), together with the exposure data will abridge the efficacy results from the Florence to the Floret study and will confirm that potential PK deviation, if any, is of no clinical relevance. Conclusion : The present PK/PD approach allows reducing the number of blood samples from each patient, in particular the lowest aged pediatric patients, while replacing a conventionally designed PK study and a robust sized Phase III study in pediatrics. By bridging PK/PD data, the Floret study not only will allow Febuxostat to rapidly address an unmet medical need in a vulnerable population, but it offers a model - whenever applicable - to be adopted to accelerate new drugs availability to the pediatric population while fully complying with regulatory requirements and minimize the number of patients in clinical trials. Disclosures Spina: Menarini Ricerche SpA: Consultancy. Off Label Use: Febuxostat in pediatric Tumor lysis syndrome. Mazzei: Menarini Ricerche SpA: Employment. Baldini: Menarini Ricerche SpA: Employment. Pedretti: Menarini Ricerche SpA: Employment. Mezzalana: Menarini Ricerche SpA: Employment. Matera: Menarini Ricerche SpA: Employment. Manunta: Menarini Ricerche SpA: Employment. Calamai: Menarini Ricerche SpA: Employment. Scordari: Menarini Ricerche SpA: Employment. Scartoni: Menarini Ricerche SpA: Employment. Capriati: Menarini Ricerche SpA: Employment. Simonelli: Menarini Ricerche SpA: Employment.