Population Pharmacokinetic Analysis of Rivipansel in Healthy Subjects and Subjects with Sickle Cell Disease.

ABSTRACT

BACKGROUND: Sickle cell disease is an inherited blood disorder with reduced blood-carrying capacity. It is associated with a tendency to form microclots in blood vessels, leading to painful episodes known as a vaso-occlusive crisis. Rivipansel is a pan-selectin inhibitor being studied for the treatment of a vaso-occlusive crisis in patients with sickle cell disease. METHODS: A population pharmacokinetic model of rivipansel plasma and urine concentrations was constructed using a two-compartment model and data from nine different clinical studies. Creatinine clearance was calculated using the Schwartz formula for children and the Chronic Kidney Disease Epidemiology Collaboration formula for adults. Urine volume and concentration of the study drug in urine from subjects in five clinical studies were used to estimate renal and nonrenal clearance. RESULTS: Rivipansel drug concentrations were well described by the model. The post hoc estimates of average steady-state concentrations were predicted to be similar for the adult and pediatric cohorts of the pivotal phase III study. Parameter estimates showed almost exclusively renal excretion of rivipansel, which is consistent with the known properties of the drug. CONCLUSIONS: The pharmacokinetics of rivipansel was well characterized by a two-compartment population pharmacokinetic model. Our results illustrate the important role of simulations in optimizing a potential drug dosing regimen for patients with sickle cell disease and progressive renal impairment.