Pharmacokinetics of Ticagrelor in Infants and Toddlers Aged <24 Months with Sickle Cell Disease

Background: There is a significant unmet need for treatments to reduce vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Until recently, the only pharmacological treatment approved for reduction of VOCs was hydroxyurea (hydroxycarbamide), and is recommended for children ≥9 months old with SCD. L-glutamine is approved for the reduction of acute complications of SCD in children ≥5 years old, although symptoms can start as early as 5 months of age. Inhibition of platelet activation has been proposed as a potential therapeutic option for SCD. The rationale for the use of antiplatelet therapies in SCD management is based on evidence that platelets participate in the vaso-occlusive process and that platelet activation correlates with the frequency of pain episodes (Ataga et al, 2012). Platelets are activated during the non-crisis steady state (Lee et al, 2006). The antiplatelet drug ticlopidine, which has a similar mechanism of action as ticagrelor (prevention of adenosine diphosphate [ADP]-mediated platelet activation), significantly reduced the frequency of VOCs in patients with SCD (Cabannes et al, 1984). In the phase III DOVE study in pediatric patients, the platelet inhibitor prasugrel was shown to result in a numerical reduction in VOC events with fewer painful crises in the prasugrel group (66%) versus placebo (72%); however, the differences versus placebo did not reach statistical significance (Heeney et al, 2016). Of note is that the prasugrel doses used in DOVE only resulted in a mean platelet inhibition of ~20% (Jakubowski et al, 2017). The low platelet inhibition may have contributed to the lack of efficacy in this study (Heeney et al, 2016). Ticagrelor is an oral, direct-acting, selective, reversibly-binding P2Y12 receptor antagonist that prevents ADP-mediated platelet activation and aggregation. Ticagrelor was approved in 2010 to reduce the rate of cardiovascular death, myocardial infarction, and stroke in adult patients with acute coronary syndromes, and is currently approved in >100 countries. A program is currently ongoing to assess the potential therapeutic benefits of ticagrelor in reducing the occurrence of VOCs in children with SCD. A phase III study (HESTIA3; NCT03615924) is underway to evaluate the efficacy of ticagrelor in reducing the rate of VOCs, as well as the safety and tolerability of ticagrelor versus placebo in SCD pediatric patients 2 to