Caplacizumab Model-Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life-threatening autoimmune thrombotic microangiopathy. Caplacizumab, evaluated in phase II and III studies in adults, shortens the time to platelet count response and reduces aTTP exacerbations, has a favorable safety profile, and can potentially reduce refractoriness and mortality associated with aTTP. Since no children with aTTP were enrolled in these clinical trials, caplacizumab has been initially approved for use only in adult patients with aTTP (10 mg). Pediatric dosing recommendations were developed using model-based simulations. A semimechanistic pharmacokinetic/pharmacodynamic population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) following intravenous and subcutaneous administration of caplacizumab in different adult populations, at various dose levels, using nonlinear mixed-effects modeling. Based on the allometrically scaled pharmacokinetic/pharmacodynamic model, different dosing regimens were simulated in 8000 children (aged 2-18 years). Simulated caplacizumab exposures and vWF:Ag levels across different age categories were compared to an adult reference group. A simulated daily dose of 5 mg in children weighing <40 kg and of 10 mg in children weighing ≥40 kg resulted in similar exposures and vWF:Ag suppression across age and weight groups. Despite the lack of pediatric clinical data, the results of this modeling and simulation analysis constituted the basis for the European extension of indication for caplacizumab (10 mg) to adolescents aged >12 years and with a body weight ≥40 kg. This represents a rare case in which regulatory authorities have deemed a modeling and simulation study robust enough to approve a variation of indication.