Abstract Number: PB0851
Meeting: ISTH 2021 Congress
Background: For acquired thrombotic thrombocytopenic purpura (aTTP), the dosing recommendation of caplacizumab is a loading dose of 10 mg intravenous (IV) bolus prior to therapeutic plasma exchange (TPE), followed by 10 mg daily subcutaneous (SC) doses starting from the end of the first TPE and for ≥30 days after the last daily TPE.
Aims: To use pharmacokinetic (PK) and pharmacodynamic (PD) simulations to evaluate the standard regimen of caplacizumab regarding the effect of the IV loading dose prior to TPE and the frequency of the maintenance SC dosing regimen after TPE.
Methods: An integrated PK/PD model was previously developed to describe the interaction between caplacizumab and von Willebrand factor (VWF) using nonlinear mixed effects modeling. The model was used to simulate PK and PD profiles for different scenarios (Table).
Results: The simulations suggest that the IV loading dose appears to be essential for rapid and sustained suppression of VWF levels during the initial hours of treatment. Omitting the IV loading dose, or administering a SC loading dose, leads to a delay in achieving optimal exposure required for the inhibition of VWF-platelet interactions.
In addition, the simulations confirm that VWF levels are sensitive to plasma caplacizumab concentrations. Non-daily dosing in the post-TPE period decreases drug exposure and leads to higher and more fluctuating VWF levels, which could expose patients with aTTP to the risk of suboptimal or incomplete inhibition of microthrombi formation. The effects are apparent with every second day dosing and become even more pronounced with every third day dosing.
Conclusions: The simulations confirm the importance of the IV loading dose of caplacizumab prior to TPE and the maintenance of a daily SC dosing regimen after TPE in ensuring that consistent and sufficient drug exposure and neutralization of VWF are achieved in patients with aTTP.
|Scenario||Loading dose||After TPE dosing|
|4||IV||Every second day|
|5||IV||Every third day|
|IV, intravenous; SC, subcutaneous; TPE, therapeutic plasma exchange.|
To cite this abstract in AMA style:Sou T, Callewaert F, de Passos Sousa R, Sargentini-Maier ML. PK/PD Modeling and Simulations Highlight the Importance of the Intravenous Loading Dose and Daily Dosing Regimen with Caplacizumab for Patients with aTTP [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/pk-pd-modeling-and-simulations-highlight-the-importance-of-the-intravenous-loading-dose-and-daily-dosing-regimen-with-caplacizumab-for-patients-with-attp/. Accessed August 16, 2022.
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