Background: Lucerastat, an inhibitor of glucosylceramide synthase, has the potential to restore the balance\nbetween synthesis and degradation of glycosphingolipids in glycolipid storage disorders such as Gaucher disease\nand Fabry disease. The safety, tolerability, and pharmacokinetics of oral lucerastat were evaluated in two separate\nrandomized, double-blind, placebo-controlled, single- and multiple-ascending dose studies (SAD and MAD, respectively)\nin healthy male subjects.\nMethods: In the SAD study, 31 subjects received placebo or a single oral dose of 100, 300, 500, or 1000 mg lucerastat.\nEight additional subjects received two doses of 1000 mg lucerastat or placebo separated by 12 h. In the MAD study,\n37 subjects received placebo or 200, 500, or 1000 mg b.i.d. lucerastat for 7 consecutive days. Six subjects in\nthe 500 mg cohort received lucerastat in both absence and presence of food.\nResults: In the SAD study, 15 adverse events (AEs) were reported in ten subjects. Eighteen AEs were reported\nin 15 subjects in the MAD study, in which the 500 mg dose cohort was repeated because of elevated\nalanine aminotransferase (ALT) values in 4 subjects, not observed in other dose cohorts. No severe or serious\nAE was observed. No clinically relevant abnormalities regarding vital signs and 12ââ?¬â??lead electrocardiograms\nwere observed. Lucerastat Cmax values were comparable between studies, with geometric mean Cmax 10.5\n(95% CI: 7.5, 14.7) and 11.1 (95% CI: 8.7, 14.2) Ã?¼g/mL in the SAD and MAD study, respectively, after 1000 mg\nlucerastat b.i.d. tmax (0.5 ââ?¬â?? 4 h) and t1/2 (3.6 ââ?¬â?? 8.1 h) were also within the same range across dose groups in\nboth studies. Using the Gough power model, dose proportionality was confirmed in the SAD study for Cmax\nand AUC0ââ?¬â??âË?ž, and for AUC0 ââ?¬â??12 in the MAD study. Fed-to-fasted geometric mean ratio for AUC0ââ?¬â??12 was 0.93\n(90% CI: 0.80, 1.07) and tmax was the same with or without food, indicating no food effect.\nConclusions: Incidence of drug-related AEs did not increase with dose. No serious AEs were reported for any\nsubject. Overall, lucerastat was well tolerated. These results warrant further investigation of substrate reduction\ntherapy with lucerastat in patients with glycolipid storage disorders.
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