Background and Objective

Deficiencies of enzymes acting downstream of glucosylceramide synthase (GCS) can cause severe substrate accumulation. Venglustat is a small-molecule, brain-penetrant GCS inhibitor under investigation for multiple diseases involving pathogenic glycosphingolipid accumulation. Here, we evaluate the pharmacokinetics, safety, and tolerability of venglustat in healthy Chinese volunteers.

Methods

Study PKM16116 was a phase I, single-center, non-randomized, open-label study to investigate the pharmacokinetics, safety, and tolerability of a single 15 mg dose of orally administered venglustat in healthy Chinese volunteers aged 18 to 45 years.

Results

A total of 14 volunteers (7 male; 7 female) with a body mass index from 20.9 kg/m² to 27.1 kg/m² were enrolled. The median time to reach the venglustat maximum plasma concentration was 2.50 h post-dose. The mean terminal half-life of venglustat was 30.6 ± 7.40 h. The mean systemic exposures across all participants were 60.3 ± 17.3 ng/mL for the maximum plasma concentration, and 2280 ± 697 ng·h/mL for the area under the plasma concentration–time curve extrapolated to infinity. There were no relevant differences in venglustat pharmacokinetics between male and female volunteers. A post hoc cross-study comparison analysis showed comparable venglustat pharmacokinetics in Chinese and non-Chinese volunteers. Venglustat was safe and well tolerated in the current study (a total of five Grade 1 treatment-emergent adverse events were reported in three volunteers).

Conclusion

Venglustat showed a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single oral 15 mg dose.

Clinical Trial Registry no.

CTR20201012 (http://www.chinadrugtrials.org.cn) registered on 24 February 2021 and ChiCTR2200066559 (http://www.chictr.org.cn) retrospectively registered on 9 December 2022.