Walsh Ryan R, Damle Nitin K, Mandhane Sanjay, Piccoli Steven P, Talluri Ravi S, Love Damon, Yao Siu-Long, Ramanathan Vikram, Hurko Orest
Sun Pharma Advanced Research Company Ltd, Cranbury, NJ, USA.
Sun Pharma Advanced Research Company Ltd, Mumbai, India.
Parkinsonism Relat Disord. 2023 Mar;108:105281. doi: 10.1016/j.parkreldis.2023.105281. Epub 2023 Jan 14.
Preclinical evidence suggests that c-Abl is critical in the pathogenesis of Parkinson's Disease (PD). Vodobatinib (K0706) is a potent, specific Abl kinase inhibitor currently being developed for the treatment of PD. In previously reported studies, nilotinib, a multikinase c-Abl inhibitor, did not show clinical activity as evidenced by no improvement of symptoms or the rate of decline after one to six months of treatment at the maximum permissible dose, presumably because of insufficient CNS penetration. Here we report clinical PK and safety data for vodobatinib.
To determine safety, plasma PK, and CSF penetration of vodobatinib in healthy volunteers and PD subjects following oral administration, and compare CSF levels to in vitro concentrations required for c-Abl inhibition relative to data reported for nilotinib.
Inhibition of c-Abl kinase activity and c-Abl binding affinity were first assessed in vitro. Healthy human volunteers and PD patients received various oral doses of vodobatinib once-daily for seven and fourteen days respectively, to assess safety, and plasma and CSF PK.
In in vitro assays, vodobatinib was more potent (kinase IC = 0.9 nM) than nilotinib (kinase IC = 15-45 nM). Administration of vodobatinib 48, 192 and 384 mg to healthy subjects for 7 days yielded mean C values of 1.8, 11.6, and 12.2 nM respectively, with the two highest doses exceeding the IC over the entire dosing interval. C values were 6-8 times greater than the IC. Comparable CSF levels were observed in PD patients. All doses were well tolerated in both cohorts.
Based on achieved CSF concentrations, the potential for c-Abl inhibition in the brain is substantially higher with vodobatinib than with nilotinib. The CSF PK profile of vodobatinib is suitable for determining if c-Abl inhibition will be neuroprotective in PD patients.
临床前证据表明，c-Abl在帕金森病（PD）的发病机制中起关键作用。伏多巴替尼（K0706）是一种强效、特异性的Abl激酶抑制剂，目前正被开发用于治疗PD。在先前报道的研究中，多激酶c-Abl抑制剂尼罗替尼未显示出临床活性，在最大允许剂量下治疗1至6个月后症状无改善或病情恶化速率未减缓，推测原因是其对中枢神经系统的穿透性不足。在此，我们报告伏多巴替尼的临床药代动力学（PK）和安全性数据。
确定伏多巴替尼在健康志愿者和PD患者口服给药后的安全性、血浆PK及脑脊液穿透性，并将脑脊液水平与尼罗替尼报道数据中c-Abl抑制所需的体外浓度进行比较。
首先在体外评估c-Abl激酶活性抑制和c-Abl结合亲和力。健康人类志愿者和PD患者分别每日口服不同剂量的伏多巴替尼，持续7天和14天，以评估安全性、血浆和脑脊液PK。
在体外试验中，伏多巴替尼（激酶IC = 0.9 nM）比尼罗替尼（激酶IC = 15 - 45 nM）更有效。健康受试者服用48、192和384 mg伏多巴替尼7天，平均C值分别为1.8、11.6和12.2 nM，最高的两个剂量在整个给药间隔内均超过IC。C值比IC高6 - 8倍。在PD患者中观察到了相当的脑脊液水平。两个队列中的所有剂量耐受性良好。
基于所达到的脑脊液浓度，伏多巴替尼在大脑中抑制c-Abl的潜力比尼罗替尼高得多。伏多巴替尼的脑脊液PK特征适合用于确定c-Abl抑制对PD患者是否具有神经保护作用。
