Pandey Richa, Zella Julia, Clagett-Dame Margaret, Plum Lori A, DeLuca Hector F, Coyne Daniel W
Department of Medicine, Division of Nephrology, Washington University, St. Louis, Mo., USA.
Am J Nephrol. 2016;43(3):213-20. doi: 10.1159/000445756. Epub 2016 Apr 21.
Use of existing therapies for secondary hyperparathyroidism (SHPT), such as calcitriol or paricalcitol, is frequently limited by the development of hypercalcemia. 2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD; DP001) is a novel and a more potent vitamin D receptor activator (VDRA) that more selectively localizes in the parathyroid gland, and has a wider therapeutic margin in the uremic rat model than calcitriol and paricalcitol.
DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Hemodialysis patients were enrolled and dosed with 110, 220, 330, 440, or 550 ng of 2MD orally thrice weekly for 4 weeks. Responders were defined as patients having a ≥30% reduction in parathyroid hormone (PTH) from baseline, and were assessed at weeks 2 and 4.
Of 31 patients recruited, 24 completed the 4-week treatment. There was little or no reduction in PTH in the 110 and 220 ng dose cohorts. Higher dose cohorts had greater PTH suppression with more than half the patients in the 440 and 550 ng dose cohorts considered responders (≥30% PTH reduction from baseline). None had oversuppression of PTH or hypercalcemia (corrected serum calcium >10.6 mg/dl). Plasma drug concentration increased with increasing dose, and all responders achieved a 2MD concentration of ≥1.5 pg/ml. All dose levels of 2MD were well tolerated without safety concerns.
In hemodialysis patients with SHPT, 2MD, at thrice weekly oral doses of 440 and 550 ng, is well tolerated and effectively suppresses PTH without hypercalcemia. Future studies are needed to study the long-term implications of treating ESRD patients with this novel VDRA.
使用现有疗法治疗继发性甲状旁腺功能亢进症（SHPT），如骨化三醇或帕立骨化醇，常因高钙血症的发生而受到限制。2-亚甲基-19-去甲-（20S）-1α，25-二羟基维生素D3（2MD；DP001）是一种新型且更有效的维生素D受体激活剂（VDRA），它更具选择性地定位于甲状旁腺，并且在尿毒症大鼠模型中比骨化三醇和帕立骨化醇具有更宽的治疗窗。
设计、地点、参与者和测量方法：纳入血液透析患者，每周口服三次2MD，剂量分别为110、220、330、440或550 ng，共4周。反应者定义为甲状旁腺激素（PTH）较基线水平降低≥30%的患者，并在第2周和第4周进行评估。
在招募的31例患者中，24例完成了4周治疗。110和220 ng剂量组的PTH几乎没有降低或降低不明显。较高剂量组对PTH的抑制作用更强，440和550 ng剂量组超过半数的患者被视为反应者（PTH较基线水平降低≥30%）。无一例患者出现PTH过度抑制或高钙血症（校正血清钙>10.6 mg/dl）。血浆药物浓度随剂量增加而升高，所有反应者的2MD浓度均≥1.5 pg/ml。2MD的所有剂量水平耐受性良好，无安全问题。
在患有SHPT的血液透析患者中，每周口服三次440和550 ng的2MD耐受性良好，可有效抑制PTH且不会引起高钙血症。需要进一步研究以探讨用这种新型VDRA治疗终末期肾病患者的长期影响。
