Abstract：
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.
摘要：
在经典半乳糖血症（CG）患者中，醛糖还原酶(AR)将半乳糖转化为半乳糖醇。在1/2阶段，安慰剂对照研究（NCT04117711），安全,药代动力学（PK），在健康成年人（n=81）和CG患者（n=14）中，在单次和多次递增剂量（0.5-40mg/kg）后评估了govorestat的药效学（PD）。血浆和脑脊液（CSF）中的govorestat水平和半乳糖醇的血液水平，半乳糖,测量和半乳糖-1-磷酸(Gal-1p)用于群体PK和PK/PD分析。Govorestat耐受性良好。安慰剂和govorestat之间的不良事件频率相当。GovorestatPK显示了2室模型，具有顺序的零级和一阶吸收，没有人口因素的影响。govorestat的多剂量PK在0.5-40mg/kg范围内呈线性关系，和CSF水平剂量依赖性增加。消除半衰期为~10小时。PK/PD建模支持每日一次给药。安慰剂与半乳糖醇的基线变化为-15％±9％，与-19％±10％，-46%±4%，和-51%±5%，使用govorestat5、20和40mg/kg，分别,因此对于20和40mg/kg是相似的。Govorestat不影响半乳糖或Gal-1p水平。总之,govorestat显示出良好的安全性，PK,和人类的PD档案，和减少galactol水平在相同的幅度（〜50％），在大鼠模型的CG，证明了对神经系统的功效益处，行为，和眼部结果。
