Population Pharmacokinetics/Pharmacodynamics of Ticagrelor in Children with Sickle Cell Disease

• Published in: Clinical pharmacokinetics 2019-10, Vol.58 (10), p.1295-1307
• Main Authors: Amilon, Carl, Niazi, Mohammad, Berggren, Anders, Åstrand, Magnus, Hamrén, Bengt
• Format: Article
• Language: English
• Subjects: Acute coronary syndromes; Adenosine; Adolescent; Adults; Anemia, Sickle Cell - blood; Anemia, Sickle Cell - drug therapy; Anemia, Sickle Cell - metabolism; Blood; Blood platelets; Cardiovascular disease; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Internal Medicine; Linux; Male; Medicine; Medicine & Public Health; Models, Biological; Original Research Article; Patients; Pediatrics; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Platelet Aggregation Inhibitors - blood; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Population; Purinergic P2Y Receptor Antagonists - blood; Purinergic P2Y Receptor Antagonists - pharmacokinetics; Purinergic P2Y Receptor Antagonists - pharmacology; Sickle cell disease; Ticagrelor - blood; Ticagrelor - pharmacokinetics; Ticagrelor - pharmacology
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-019-00758-0

Background and Objective Ticagrelor, a reversible P2Y 12 platelet inhibitor, is under investigation as a sickle cell disease (SCD) therapy in children. HESTIA1 (NCT02214121) was the first ticagrelor study generating pharmacokinetic (PK), pharmacodynamic (PD, P2Y 12 reactivity units [PRU]), and safety data in 45 pediatric SCD patients. Population PK and PK/PD relationships for ticagrelor were quantified using a PK approach. Methods An adult population PK model was refined to describe ticagrelor and AR–C124910XX (active metabolite) plasma concentration and time data over a wide range of single/repeated ticagrelor doses (0.125–2.25 mg/kg). Population PK/PD modeling was used to describe the time course and extent of platelet inhibition. Demographic covariate relationships were investigated. Results The final population PK model adequately described ticagrelor and AR-C124910XX plasma concentrations over time. An allometric body weight relationship between ticagrelor and AR-C124910XX clearances and volumes of distribution was used. Significant covariates for ticagrelor were sex (relative bioavailability) and cholecystectomy (central volume of distribution). Estimated oral clearances (35 kg patient; median bodyweight) were 22.8 L/h (ticagrelor) and 9.97 L/h (AR-C124910XX). The final population PK/PD model well-described the time course and extent of platelet inhibition. Estimated baseline PRU was 283, maximum PRU effect was fixed at 1, and the ticagrelor concentration for half-maximum PRU effect was 233 nmol/L. Conclusions These analyses offer the first quantitative characterization of the dose-exposure-response relationship for ticagrelor in pediatric SCD patients. This model-based approach may be used to inform dose selection and design of subsequent studies that aim to define ticagrelor safety and efficacy in pediatric SCD patients.