rADAMTS13 is a recombinant form of the endogenous ADAMTS13. ADAMTS13 is a plasma zinc metalloprotease that regulates the activity of von Willebrand factor (VWF) by cleaving large and ultra-large VWF multimers to smaller units and thereby reducing the platelet binding properties of VWF and its propensity to form microthrombi. rADAMTS13 is expected to reduce or eliminate the spontaneous formation of VWF-platelet microthrombi that leads to platelet consumption and thrombocytopenia in patients with cTTP.
Anti-drug antibodies (ADA) were very commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.
The pharmacokinetic (PK) profile of apadamtase alfa was determined based on clinical study ADAMTS13 activity data analyses.
Following single-dose intravenous administration of apadamtase alfa at 5 IU/kg, 20 IU/kg, and 40 IU/kg to adults and adolescents, dose-related increases in individual ADAMTS13 activity were observed and reached a maximum at approximately 1 hour post-administration or earlier. At clinical dose of 40 IU/kg the mean (SD) half-life and mean residence time (MRT) in adults and adolescents were 47.8 (13.7) hours and 63.8 (16.0) hours, respectively.
The population PK parameters of ADAMTS13 activity following intravenous administration of apadamtase alfa at 40 IU/kg in adults, adolescents, and younger children are described in the following table.
Pharmacokinetic parameters of ADAMTS13 activity following intravenous administration of apadamtase alfa in cTTP patients:
| Parameter (unit) | Mean (SD) Min; Max (N=83) |
| Cmax (IU/mL) | 1.13 (0.29) 0.72; 2.29 |
| AUC (IU*h/mL) | 72.8 (37.4) 38.7; 274 |
| Duration ADAMTS13 activity above 10% (days) | 8.85 (2.45) 4.51; 14.0 |
AUC = area under ADAMTS13 activity-time curve; Cmax = maximum ADAMTS13 activity.
Note: 1 IU/mL ADAMTS13 activity corresponds to 100% average normal activity.
Apadamtase alfa intravenous administration at 40 IU/kg resulted in approximately greater than 5-fold higher ADAMTS13 activity exposures (Cmax, AUC, and duration above 10% ADAMTS13 activity) and lower variability when compared to plasma-based therapies.
Besides body-weight dosing regimen, no intrinsic factors such as age, gender, race, baseline estimated glomerular filtration rate (eGFR), and baseline bilirubin were identified as covariates impacting ADAMTS13 PK.
ADAMTS13 activity PK characteristics (MRT, steady-state volume of distribution [Vss], and clearance [CL]) were similar across age groups in patients with cTTP. Body weight-based apadamtase alfa dosing provides similar ADAMTS13 activity PK parameters (Cmax and average ADAMTS13 activity [Cave]) across the different age groups including paediatric patients <12 years of age.
In infants <10 kg body weight, median duration above 10% ADAMTS13 activity was estimated to be shorter (approximately 5-6 days) compared to adults (approximately 10 days).
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, single dose toxicity, toxicity to reproduction and development, local tolerance and immunogenicity. Studies to evaluate the mutagenic and carcinogenic potential of rADAMTS13 have not been performed.
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