Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life-threatening autoimmune blood clotting disorder, with a much lower incidence in children compared to adults. Caplacizumab has been evaluated in phase 2 and phase 3 randomized clinical trials in adult patients with aTTP.
As no pediatric patients were enrolled in clinical trials with caplacizumab, dosing recommendations were developed using model-based simulations for this population.
A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) 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 non-linear mixed effects modeling. Simulations based on the allometrically scaled PKPD model were performed to establish a suitable dosing regimen in adolescents and children >2 years.Eight age categories including 1000 individuals in each category were defined, and corresponding individual body weights were sampled from the National Health and Nutrition Examination Survey database. The simulated exposure levels of caplacizumab in the different age categories were compared to those predicted in adults.
The simulations of exposure indicate that a flat 10 mg daily dosing would result in higher exposure in children with a low body weight, primarily children under 10 years of age. A dose adjustment to 5 mg daily to children with a body weight <40 kg would result in an on average similar exposure across age and weight groups. The body weight adjusted dosing is also predicted to result in highly similar suppression of vWF:Ag across the different age groups.
The recommended dose in adolescents 12-18 years with a body weight ≥40 kg is 10 mg, and 5 mg if <40 kg. Since no differences in vWF:Ag suppression are expected based on differences in age, the same dosing recommendation applies for children 2-12 years, 10 mg if the body weight is ≥40 kg and 5 mg if <40 kg.