Abstract
Background: Rivipansel is a pan-selectin inhibitor in phase 3 development for treatment of sickle cell disease vaso-occlusive crises. Previous studies have shown almost complete elimination of unchanged drug in urine following an intravenous (IV) infusion. The objective of this study was to evaluate the effect of varying degrees of renal impairment on the pharmacokinetics (PK), safety, and tolerability of rivipansel.
Methods: A single 840-mg dose of open-label rivipansel was administered IV over 20 minutes to 7 subjects with mild, 7 with moderate, and 7 with severe renal impairment, and to 7 healthy subjects with normal renal function. Classification of renal impairment groups was based on the Cockroft-Gault estimated glomerular filtration rate (CGeGFR): 60-89 mL/min (mild), 30-59 mL/min (moderate), and <30 mL/min (severe). Normal renal function was CGeGFR ≥90 mL/min. Plasma and urine samples were collected for 96 hours postdose and analyzed by validated LC-MS/MS methods. Pharmacokinetic parameters were estimated using noncompartmental modeling. ANOVA was used to assess the effect of renal impairment on PK parameters.
Results: All 28 subjects completed the study. A summary of PK parameters is presented in Table 1. Overall rivipansel exposure was greater in subjects with mild, moderate, and severe renal impairment, with values 1.4×, 2.3×, and 5.5× that of subjects with normal renal function, respectively. Renal clearance decreased with decreasing renal function. Total clearance was lower by 31%, 56%, and 82% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function group. Five treatment-emergent adverse events (TEAEs) were reported in 3 subjects in the mild renal impairment group, and 3 TEAEs were reported in 2 subjects in the severe renal impairment group. None of the TEAEs reported was considered to be treatment-related.
Conclusions: Greater rivipansel exposure and decreased clearance were observed in subjects with renal impairment compared with subjects with normal renal function. A single 840-mg IV dose of rivipansel was well tolerated in all groups.
Tammara:Pfizer Inc.: Employment. Ryan:Pfizer Inc.: Employment. Plotka:Pfizer Inc.: Employment. Shafer:Pfizer Inc.: Employment. Wei:Pfizer Inc.: Employment. Readett:Pfizer Inc.: Employment. Fang:Pfizer Inc.: Employment. Korth-Bradley:Pfizer Inc.: Employment.
