Lucerastat, an Iminosugar for Substrate Reduction Therapy: Pharmacokinetics, Tolerability, and Safety in Subjects With Mild, Moderate, and Severe Renal Function Impairment.

Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for substrate reduction therapy in glycosphingolipid storage disorders such as Fabry disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main route of elimination was renal. The pharmacokinetics, tolerability, and safety of lucerastat were evaluated in subjects with mild (group A), moderate (group B), and severe (group C) renal impairment. Group D included healthy subjects. Thirty-two subjects (8 per group) were included in this single-center, open-label study and received a single oral dose of 1000 mg lucerastat in groups A and B and 500 mg in groups C and D. The degree of renal impairment of the subjects was based on estimated glomerular filtration rate. Plasma lucerastat concentrations (dose-corrected) were higher in groups B and C compared to group D. The elimination phase half-life was slower in groups B (9.6 hours) and C (16.1 hours) compared to group D (7.0 hours). Increased exposure to lucerastat was observed in subjects from groups B and C with ratio of geometric means (90%CI) of 1.60 (1.29, 1.98) for group B vs D and 3.17 (2.76, 3.65) for group C vs D. There were no clinically relevant abnormalities in vital signs, 12-lead electrocardiograms, and clinical laboratory values. Four nonserious adverse events were reported by 4 subjects (1 in group A, 3 in group D). Lucerastat was well tolerated in all dose groups. Dose adjustment is warranted in subjects with moderate and severe renal impairment.