Caplacizumab Model-Based Dosing Recommendations In Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura
Tomás Sou (1), Emma Hansson (2), Martin Bergstrand (2), Filip Callewaert (3), Rui de Passos Sousa (4), Laura Sargentini (1)
(1) Sanofi, Ghent, Belgium; (2) Pharmetheus, Uppsala, Sweden; (3) Sanofi, Diegem, Belgium; (4) Sanofi, Lisbon, Portugal
Objectives: 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. The efficacy and safety of caplacizumab, a Nanobody® that inhibits von Willebrand factor (VWF)-platelet interaction, have been previously established in Phase 2 (TITAN; ClinicalTrials.gov number, NCT01151423; funded by Ablynx) and Phase 3 (HERCULES; ClinicalTrials.gov number, NCT02553317; funded by Ablynx) randomized clinical trials in adult patients with aTTP [1,2]. Since no pediatric patients were enrolled in clinical trials with caplacizumab, dosing recommendations were developed using model-based simulations for this population.
Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) population model has been developed describing the interaction between caplacizumab and VWF 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 of age. Eight age categories including 1000 individuals in each category (2-year intervals between age 2 to 18 years) 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 of a simulated population of 1000 adult patients with aTTP generated by assuming the same covariate distribution as that observed in the TITAN and HERCULES trials [1,2]. Expression of VWF, baseline VWF:Ag levels, affinity of caplacizumab to VWF, and gender proportion were assumed to be similar between children and adults with aTTP based on published literature [3,4]. The simulations were performed using NONMEM version 7.3.0. Data management and post-processing of NONMEM output were performed in R version 3.3.3.
Results: 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, compared with older age categories and adults. A dose adjustment to 5 mg daily in children with a body weight <40 kg would result in an on average similar exposure across age and weight groups and not show substantial deviation from that in adults. The body weight adjusted dosing is also predicted to result in highly similar suppression of VWF:Ag across the different age groups; the predicted median for caplacizumab steady-state area under the curve in each 2-year age category is expected to be within ±8% of the median value for the adult population with adjusted dosing.
Conclusions: Based on the PKPD model simulation, the recommended dose of caplacizumab in adolescents 12–18 years of age is 10 mg in those with a body weight ≥40 kg, and 5 mg in those with body weight <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 of age, 10 mg if the body weight is ≥40 kg and 5 mg if <40 kg.
This study was funded by Ablynx, a Sanofi company.
The data were previously presented as an abstract at 24th Congress of the European Hematology Association, June 13–16, 2019.
TS, FC, RPS and LS are employees of Sanofi. EH and MB are employees of Pharmetheus AB, contracted as external consultants by Ablynx / Sanofi.
 Peyvandi F, et al. N Engl J Med. 2016;374(6):511-522.
 Scully M, et al. N Engl J Med. 2019;380(4):335-346.
 Reese JA, et al. Pediatr Blood Cancer. 2013;60(10):1676-1682.
 Sosothinkul D, et al. J Pediatr Hematol Oncol. 2007;29(1):19–22.