Prasugrel in Children with Sickle Cell Disease: Pharmacokinetic and Pharmacodynamic Characteristics from an Open-Label, Adaptive-Design, Dose-Ranging Study

There are few approved treatments for children with sickle cell disease (SCD) who experience painful vaso-occlusive crises (VOC). Evidence suggests a pathophysiologic role for platelets in SCD, in general, and in VOC, specifically. Thrombocytosis is common, and markers of platelet activation, are elevated in both children and adults with SCD. This activation may be mediated by adenosine diphosphate (ADP) released from hemolysis of sickled erythrocytes. Accordingly, platelets are a rational therapeutic target to explore with the aim to reduce the frequency and severity of VOC. Therefore, we studied prasugrel, an irreversible P2Y₁₂ ADP receptor antagonist that inhibits platelet activation and aggregation, in children with SCD. The primary objective was to identify doses of prasugrel that produced a 30–50% inhibition of platelet activation for use in a pediatric phase 3 study of efficacy.

We conducted a phase 2, open-label, multi-center, adaptive-design, dose-ranging, pharmacokinetic (PK) and pharmacodynamic (PD) study of prasugrel in children with SCD. Males and females 2–17 years of age (inclusive) with SCD (HbSS and HbSβ⁰-thalassemia genotypes) were eligible. Treatment was initiated with single prasugrel doses expected to have no effect and dosage was increased in accordance with an adaptive design for improved safety and dosage identification. Patients were to receive up to 3 single doses of prasugrel with the second and third doses being administered 14±4 days after the previous dose. Doses of prasugrel were increased or decreased based on the PD response to previous doses in the same patient and/or other patients. Demographic characteristics were also considered for dose assignment in order to balance age, body weight, and sex across the dose range that produced a 30–50% inhibition of platelet aggregation.

Platelet inhibition was evaluated by the VerifyNow™ (VN) P2Y₁₂ assay and the vasodilator-associated simulated phosphoprotein (VASP) phosphorylation assay. These PD measures were assessed at screening and 4 hours after each single prasugrel dose. Venous blood samples were collected 0.5 h, 1 h, 1.5 h, 2 h, and 4 h post-dose for PK analysis of prasugrel's active metabolite to calculate the area under the concentration-time curve (AUC). The PK/PD analyses were conducted to describe the relationship between prasugrel's active metabolite AUC and platelet inhibition. Spearman correlation statistics were used to assess the relationship between dose and PD parameters.

A total of 24 patients, ranging in age from 4 to 17 years of age, received at least one dose of prasugrel. The mean age was 11.0 years; 58.3% were female; 87.5% had HbSS and 12.5% had HbSβ⁰-thalassemia. Body weight ranged from 14.4 to 80.1 kg. Patients received single doses of prasugrel ranging from 0.03 to 0.60 mg/kg. A single-dose range of 0.30–0.50 mg/kg produced mean 30–50% inhibition in platelet activation by the VN assay whereas a single-dose range of 0.40–0.50 mg/kg produced mean 30–50% inhibition in the VASP assay. Minimal PD response was observed at single doses, up to approximately 0.25 mg/kg. Above 0.25 mg/kg, PD response increased with dose. The single 0.60 mg/kg dose produced >50% inhibition by both VN and VASP assays.

In general, higher doses resulted in increased exposure to prasugrel's active metabolite. Increased variability in exposure and in PD response was seen at higher doses. The PD results demonstrate correlation between dose and 4-hour VN P2Y₁₂ percent inhibition. Prasugrel appeared to be safe and well tolerated in this small patient sample. Three serious adverse events occurred in 2 patients; none of which were considered possibly related to prasugrel. No hemorrhagic events were observed, and no subjects discontinued participation due to an adverse event.

These single-dose data will contribute to a population modeling strategy that targets the desired steady state range of platelet inhibition (30–50%) for a subsequent phase 3 clinical trial of the efficacy and safety of prasugrel for the reduction of VOC in children with SCD. Daily maintenance doses will be evaluated in a subsequent part of the current study.

Styles:Eli Lilly and Company: Consultancy. Off Label Use: Inhibition of platelet activation by prasugrel in pediatric patients with sickle cell disease. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Heiselman:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heeney:Novartis: Consultancy, Research Funding; Eli Lilly and Company: Research Funding; Pfizer: Consultancy. Redding-Lallinger:Eli Lilly and Company: Research Funding. Small:Eli Lilly and Company: Employment, Equity Ownership. Moser:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership.