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.

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.

Impact of Sugammadex Versus Neostigmine Reversal on Postoperative Recovery Time in Patients With Obstructive Sleep Apnea Undergoing Bariatric Surgery: A Double-Blind, Randomized Controlled Trial.

BACKGROUND: Residual neuromuscular blockade can be associated with serious postoperative complications. Sugammadex is a newer neuromuscular blocking drug (NMBD) reversal agent that rapidly and completely reverses rocuronium. Whether sugammadex has any advantages over neostigmine in morbidly obese patients with obstructive sleep apnea (OSA) is unclear. We investigated whether sugammadex would reduce discharge time from the operating room (OR) compared with neostigmine in morbidly obese patients with OSA undergoing bariatric surgery. METHODS: This was a prospective, double-blinded randomized controlled superiority trial with 2 parallel groups. Patients were randomized 1:1 into reversal of NMBD with sugammadex or neostigmine. Our inclusion criteria were morbidly obese adult patients with OSA undergoing elective bariatric surgery under general anesthesia. Our exclusion criteria were allergy to rocuronium, sugammadex or neostigmine, malignant hyperthermia, hepatic or renal insufficiency, neuromuscular diseases, and an inability to give consent. The primary outcome was the time from administration of the NMBD reversal agent to discharge from the OR. Secondary outcomes included the time from administration of the NMBD reversal agent to the time the patient opened eyes to command, and the time to extubation. The Mann-Whitney test was used to compare the outcomes between treatment groups. RESULTS: We randomized 120 patients into 2 groups of 60 patients. Overall median body mass index (BMI) was 48.1 kg/m2 ([interquartile range, IQR]) [43.0-53.5]. The time from drug administration to discharge from OR was 13.0 minutes [10.0-17.0] in the sugammadex group and 13.5 minutes [11.0-18.3] in the neostigmine group (P = .27). The treatment effect estimate with a bootstrapped 95% confidence interval [CI] for time from admission to discharge from OR was -0.5 [-2.5 to 3]. No differences were observed in postoperative complications and other secondary outcomes. CONCLUSIONS: No difference was observed in OR discharge time in morbidly obese patients with OSA when sugammadex was administered instead of neostigmine.