Impact of the organic cation transporter 2 inhibitor cimetidine on the single-dose pharmacokinetics of the glucosylceramide synthase inhibitor lucerastat in healthy subjects

• Published in: European journal of clinical pharmacology Vol. 76; no. 3; pp. 431 - 437
• Main Authors: Boof, Marie-Laure, Halabi, Atef, Ufer, Mike, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2020; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Ceramide glucosyltransferase; Cimetidine; Genotypes; Oct-2 protein; Oral administration; Organic cation transporter; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology/Toxicology; Renal function; Fabry disease; Drug-drug interaction; Pharmacokinetics; Lucerastat; OCT2
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-019-02808-9

Purpose Lucerastat is an orally available glucosylceramide synthase inhibitor with a potential to provide substrate reduction therapy for Fabry patients independent of their α-galactosidase A genotype. In humans, lucerastat is mainly eliminated as unchanged parent compound through renal excretion both by active secretion and passive filtration. In vitro studies indicated that lucerastat is a substrate of human organic cation transporter 2 (OCT2) mainly expressed in the kidney. Methods Therefore, this clinical study, conducted in 14 healthy male subjects, investigated the effect of 800 mg twice-daily oral administration of the OCT2 inhibitor cimetidine at steady state on the single-dose pharmacokinetics (PK) of 500 mg lucerastat. The safety and tolerability of lucerastat administered alone and concomitantly with cimetidine were also evaluated. Results Exposure to lucerastat was slightly higher upon co-administration of cimetidine indicated by geometric mean area under the plasma concentration-time curve from zero to infinity (AUC 0–∞ ) ratio of 1.22 (90% confidence interval [CI] 1.16–1.28). Cimetidine delayed the time to reach maximum lucerastat concentrations ( t max ) by 1 h but did not affect its elimination half-life ( t ½ ) or maximum plasma concentration ( C max ) as geometric mean ratios were 1.00 (0.91–1.10) and 1.04 (0.92–1.17), respectively, at cimetidine steady state. Lucerastat was safe and well tolerated when given alone and in combination with cimetidine. Conclusion These results indicate that the single-dose PK of lucerastat are not changed to a clinically relevant extent by cimetidine-mediated OCT2 inhibition, allowing the concomitant use of OCT2 inhibitors with lucerastat without any need for dose adjustment. Trial registration EudraCT: 2017-003725-14; ClinicalTrials.gov: NCT03380455