Safety, Pharmacokinetics, and Pharmacodynamics of the New Aldose Reductase Inhibitor Govorestat (AT-007) After a Single and Multiple Doses in Participants in a Phase 1/2 Study.

Autor: Perfetti R; Applied Therapeutics Inc., New York, USA., Bailey E; Applied Therapeutics Inc., New York, USA., Wang S; Applied Therapeutics Inc., New York, USA., Mills R; Quantitative Pharmacology and Pharmacometrics, ICON plc, Dublin, Ireland., Mohanlal R; Applied Therapeutics Inc., New York, USA., Shendelman S; Applied Therapeutics Inc., New York, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2024 Nov; Vol. 64 (11), pp. 1397-1406. Date of Electronic Publication: 2024 Jul 10.
DOI: 10.1002/jcph.2495
Abstrakt: In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo-controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5-40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose-1-phosphate (Gal-1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2-compartment model with sequential zero- and first-order absorption, and no effect of demographic factors. Multiple-dose PK of govorestat was linear in the 0.5-40 mg/kg range, and CSF levels increased dose dependently. Elimination half-life was ∼10 h. PK/PD modeling supported once-daily dosing. Change from baseline in galactitol was -15% ± 9% with placebo and -19% ± 10%, -46% ± 4%, and -51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal-1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes.
(© 2024 Applied Therapeutics Inc. and The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
Databáze: MEDLINE
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