Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Box 31, Ithaca, NY 14853, USA.
Cancer Chemother Pharmacol. 2011 Jan;67(1):165-71. doi: 10.1007/s00280-010-1304-2. Epub 2010 Mar 21.
High-dose calcitriol (1,25-dihydroxyvitamin D(3)) has antineoplastic activity against a range of tumors and potentiates chemotherapeutic agents. In an earlier canine study, the MTD of intravenous (i.v.) calcitriol was 3.75 μg/kg, but polysorbate-associated hypersensitivity reactions were common. Use of commercially available oral calcitriol is limited by the absence of a formulation of suitable strength to allow administration of a reasonable number of caplets. This study evaluated the bioavailability of DN101, a concentrated oral calcitriol formulation specifically developed for anticancer applications.
An open-label, single-dose, 2-way crossover study was conducted. Dogs randomly received a single 3.75 μg/kg dose of calcitriol either i.v. or oral (as DN101), followed by cisplatin (60 mg/m(2)). Three weeks later, the alternate form of calcitriol was given prior to another dose of cisplatin. Dogs received antihistamines and corticosteroids prior to both treatments. Food was withheld for 12 h before and after therapy. Serum calcitriol concentrations were measured by radioimmunoassay.
Ten tumor-bearing dogs received both i.v. and oral calcitriol. Six dogs experienced hypersensitivity reactions during i.v. calcitriol. Sequence of calcitriol administration (day-1 vs. day-21) by either i.v. or oral routes had no effect on the major calcitriol pharmacokinetic parameters. Oral calcitriol resulted in significantly lower values for AUC (P = 0.05) and prolonged T (1/2) (P = 0.003) when compared to i.v. Calcitriol oral bioavailability was highly variable among dogs (mean ± SEM, 71 ± 12.6%).
This study demonstrates that a high-dose formulation of calcitriol has a moderate bioavailability in dogs, but inter-individual variability in PK parameters is similar to that observed in people. With this bioavailability, serum concentrations of calcitriol that exhibit antitumor activity in a preclinical murine model were achieved in some dogs. Exploration of methods to minimize variation in calcitriol systemic exposure is warranted.
大剂量钙三醇（1,25-二羟维生素 D(3)）对多种肿瘤具有抗肿瘤活性，并增强化疗药物的作用。在早期的犬研究中，静脉（i.v.）钙三醇的最大耐受剂量为 3.75μg/kg，但聚山梨酯相关的过敏反应很常见。由于缺乏合适强度的制剂，商业上可获得的口服钙三醇的使用受到限制，无法给予合理数量的胶囊。本研究评估了专为抗癌应用而开发的浓缩口服钙三醇制剂 DN101 的生物利用度。
进行了一项开放标签、单剂量、2 向交叉研究。狗随机接受单次 3.75μg/kg 剂量的钙三醇静脉内（作为钙三醇）或口服（作为 DN101），随后给予顺铂（60mg/m(2)）。3 周后，给予另一种钙三醇制剂，然后再给予顺铂。在两种治疗前，狗都接受了抗组胺药和皮质类固醇治疗。在治疗前后 12 小时禁食。用放射免疫法测定血清钙三醇浓度。
10 只患有肿瘤的狗同时接受了静脉内和口服钙三醇治疗。6 只狗在静脉内钙三醇治疗期间出现过敏反应。无论是静脉内还是口服途径，钙三醇给药顺序（第 1 天与第 21 天）对主要钙三醇药代动力学参数均无影响。与静脉内相比，口服钙三醇导致 AUC（P=0.05）和 T（1/2）（P=0.003）显著降低。钙三醇口服生物利用度在狗之间高度可变（平均值±SEM，71±12.6%）。
本研究表明，高剂量钙三醇制剂在狗中有中等的生物利用度，但个体间 PK 参数的变异性与在人群中观察到的相似。在这种生物利用度下，在临床前小鼠模型中观察到具有抗肿瘤活性的钙三醇血清浓度在一些狗中得到了实现。探索最小化钙三醇全身暴露变异性的方法是值得的。
