Li Yan, Palmisano Maria, Sun Duxin, Zhou Simon
Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ 07920, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Clin Pharmacol. 2020 Jul 1;12:83-96. doi: 10.2147/CPAA.S255789. eCollection 2020.
Voclosporin, a more potent derivative of cyclosporine, has been studied extensively in patients with immunologic disorders such as psoriasis, organ transplantation, uvetitis and lupus nephritis. Although better tolerated and safer than cyclosporine, voclosporin is inferior to cyclosporine in treating psoriasis, non-inferior to tacrolimus in organ transplantation and efficacious in treating lupus nephritis.
The pharmacokinetic dispositions of voclosporin and cyclosporine in central and peripheral compartments were analyzed and correlated with their distinct clinical efficacy and safety profiles.
Both drugs demonstrated non-linear pharmacokinetics with increasing doses, more prominently at lower doses of voclosporin than at 10-fold higher doses of cyclosporine. Repeated lower dosing of voclosporin produced preferential calcineurin inhibition in and near blood circulation, leading to relatively lower cardiovascular and renal adverse effects but inferior efficacy for psoriasis compared to cyclosporine. With 10-fold higher plasma levels and deeper tissue penetration, cyclosporine has more prevalent renal and cardiac toxicities but superior efficacy to treat psoriasis.
Although the two drugs are similar in structure and mechanism of action, the high potency and low dose compounded by the non-linear disposition of voclosporin resulted in more systemic versus local calcineurin inhibition than with cyclosporine. The dispositional difference between voclosporin and cyclosporine accounted for the puzzling efficacy and safety observations in different patients and was the basis for their optimal and differential use in treating diverse immunologic disorders.
voclosporin是环孢素的一种更强效的衍生物，已在银屑病、器官移植、葡萄膜炎和狼疮性肾炎等免疫性疾病患者中进行了广泛研究。尽管voclosporin比环孢素耐受性更好、更安全，但在治疗银屑病方面不如环孢素，在器官移植方面不劣于他克莫司，在治疗狼疮性肾炎方面有效。
分析了voclosporin和环孢素在中枢和外周 compartments的药代动力学特征，并将其与它们不同的临床疗效和安全性特征相关联。
两种药物均表现出剂量增加时的非线性药代动力学，在较低剂量的voclosporin时比在高10倍剂量的环孢素时更为明显。重复给予较低剂量的voclosporin会在血液循环及其附近产生优先的钙调神经磷酸酶抑制作用，导致心血管和肾脏不良反应相对较低，但与环孢素相比，治疗银屑病的疗效较差。环孢素血浆水平高10倍且组织穿透力更强，具有更普遍的肾脏和心脏毒性，但治疗银屑病的疗效更佳。
尽管这两种药物在结构和作用机制上相似，但voclosporin的高效能和低剂量与非线性分布相结合，导致与环孢素相比，全身而非局部的钙调神经磷酸酶抑制作用更强。voclosporin和环孢素之间的分布差异解释了不同患者中令人困惑的疗效和安全性观察结果，也是它们在治疗各种免疫性疾病中优化和差异使用的基础。
