Washington University, St. Louis, MO, USA.
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI, 53706, USA.
Drugs R D. 2017 Dec;17(4):597-605. doi: 10.1007/s40268-017-0210-z.
2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D (DP001 or 2MD) is a novel, potent 1α-hydroxylated vitamin D analog that binds to the vitamin D receptor and suppresses parathyroid hormone synthesis and secretion with potential for an improved safety profile compared to existing active vitamin D analogs. The purpose of this study was to evaluate the pharmacokinetics of DP001 given orally after hemodialysis.
DP001 (550 ng) was given orally to 11 hemodialysis patients with secondary hyperparathyroidism after each dialysis session (3 times/week) for 4 weeks. Pharmacokinetic analyses were performed after the first and final dose.
After the first and final dose, the half-life of DP001 was similar (55.8 ± 13.0 and 50.8 ± 8.2 h, respectively). At 4 weeks, the time to maximum plasma concentration was 4.0 ± 0.8 h, with a concentration maximum of 3.4 ± 0.3 pg/mL. The area under the curve (0 to infinity) after the final dose was 204.3 ± 23.9 pg h/mL, and apparent volume of distribution was 2.03 ± 0.22 L/kg. At week 4, mean intact parathyroid hormone was suppressed 33% from the baseline (pre-dose) value (313 ± 52 vs 462 ± 39 pg/mL, respectively). No clinically significant changes from baseline values were found for vital signs, electrocardiogram measurements, or other laboratory parameters, including serum calcium and phosphorus.
In hemodialysis patients, DP001 has a longer half-life than existing vitamin D therapies and enables control of parathyroid hormone when administered every 2-3 days on the day of dialysis. It is effective at a lower concentration maximum and area under the curve than other clinically available vitamin D compounds. DP001 may represent a therapeutic improvement over existing compounds due to rapid and extensive distribution to its target and its long half-life enabling sustained parathyroid hormone suppression. These studies support further evaluation of DP001 in longer-term treatment of secondary hyperparathyroidism.
2-亚甲基-19-降-（20S）-1α，25-二羟维生素 D（DP001 或 2MD）是一种新型的、有效的 1α-羟化维生素 D 类似物，与维生素 D 受体结合，抑制甲状旁腺激素的合成和分泌，与现有的活性维生素 D 类似物相比，具有改善的安全性。本研究的目的是评估 DP001 在血液透析后口服的药代动力学。
11 例继发性甲状旁腺功能亢进的血液透析患者，在每次透析后（每周 3 次）给予 DP001（550ng），连续 4 周。在第 1 次和第 4 次剂量后进行药代动力学分析。
第 1 次和第 4 次剂量后，DP001 的半衰期相似（分别为 55.8±13.0 和 50.8±8.2h）。4 周时，达峰时间为 4.0±0.8h，达峰浓度为 3.4±0.3pg/mL。末次剂量后的曲线下面积（0 至无穷大）为 204.3±23.9pg·h/mL，表观分布容积为 2.03±0.22L/kg。第 4 周时，完整甲状旁腺激素与基线（预剂量）值相比抑制了 33%（分别为 313±52 与 462±39pg/mL）。生命体征、心电图测量和其他实验室参数（包括血清钙和磷）均未发现与基线值有临床意义的变化。
在血液透析患者中，DP001 的半衰期长于现有的维生素 D 治疗药物，并且可以在透析日每 2-3 天给药一次时控制甲状旁腺激素。与其他临床可用的维生素 D 化合物相比，DP001 在较低的峰浓度和曲线下面积时具有疗效。DP001 可能代表了对现有化合物的治疗改善，因为它能够快速广泛地分布到目标部位，并具有较长的半衰期，从而持续抑制甲状旁腺激素。这些研究支持在继发性甲状旁腺功能亢进的长期治疗中进一步评估 DP001。
