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Effect of Renal Function Impairment on the Pharmacokinetics, Safety, and Tolerability of the Iminosugar Sinbaglustat
Author(s) -
Melchior Meggane,
Dingemanse Jasper,
Alatrach Abir,
Feldkamp Thorsten,
Sidharta Patricia N.,
Géhin Martine
Publication year - 2021
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1808
Subject(s) - tolerability , medicine , pharmacokinetics , renal function , cmax , confidence interval , urology , urine , adverse effect , pharmacology
Sinbaglustat (ACT‐519276), a brain‐penetrating inhibitor of glucosylceramide synthase and nonlysosomal glucosylceramidase, is developed as a new therapy for lysosomal storage disorders. In the first‐in‐human study, sinbaglustat was primarily excreted unchanged in urine. This study was conducted to evaluate the effect of mild, moderate, and severe renal function impairment on the safety, tolerability, and pharmacokinetics (PK) of sinbaglustat. In this single‐center, open‐label study, 32 subjects (8 per renal function group, assessed by the Cockcroft‐Gault formula, and 8 healthy subjects) received a single oral dose of 200 mg sinbaglustat. Plasma PK parameters of sinbaglustat were derived by noncompartmental analysis. Standard safety and tolerability evaluations were analyzed descriptively. When compared with healthy subjects, C max did not present clinically relevant differences in subjects with impaired renal function, but median t max was slightly longer in subjects with moderate and severe renal function impairment. Overall, when compared with healthy subjects, exposure to sinbaglustat based on AUC 0‐t (geometric mean and 90% confidence interval) increased in subjects with mild, moderate, and severe renal function impairment by 1.2‐fold (1.08‐ to 1.36‐fold), 1.8‐fold (1.47‐ to 2.17‐fold), and 2.6‐fold (2.23‐ to 3.00‐fold), respectively. There were no clinically relevant findings on electrocardiogram, vital signs, and clinical laboratory variables. Headache was reported by 2 of 24 subjects with renal function impairment and by 2 of 8 healthy subjects. In conclusion, 200 mg of sinbaglustat was well tolerated in all groups. In future studies, a 2‐ and 3‐fold dose reduction is needed for subjects with moderate and severe renal function impairment, respectively.