John Markus R, Harfst Evita, Loeffler Juergen, Belleli Rossella, Mason June, Bruin Gerard J M, Seuwen Klaus, Klickstein Lloyd B, Mindeholm Linda, Widler Leo, Kneissel Michaela
Novartis Pharma AG, Basel, Switzerland, Novartis Corporation, East Hanover, NJ, USA.
Novartis Institutes for Biomedical Research, Basel, Switzerland and Cambridge, MA, USA.
Bone. 2014 Jul;64:204-10. doi: 10.1016/j.bone.2014.04.015. Epub 2014 Apr 24.
Antagonism of the calcium-sensing receptor in the parathyroid gland leads to parathyroid hormone (PTH) release. Calcilytics are a new class of molecules designed to exploit this mechanism. In order to mimic the known bone-anabolic pharmacokinetic (PK) profile of s.c. administered PTH, such molecules must trigger sharp, transient and robust release of PTH. The results of two early clinical studies with the orally-active calcilytic AXT914, a quinazolin-2ne derivative are reported. These were GCP-compliant, single and multiple dose studies of PK/PD and tolerability in healthy volunteers and postmenopausal women. The first study, examined single ascending doses (4 to 120 mg) and limited multiple doses (60 or 120 mgq.d. for 12 days) of AXT914. The second study was a randomized, double-blind, active- and placebo-controlled, 4-week repeat-dose parallel group study of healthy postmenopausal women (45 and 60 mg AXT914, placebo, 20 μg Forteo/teriparatide/PTH(1-34) fragment). AXT914 was well tolerated at all doses and reproducibly induced the desired PTH-release profiles. Yet, 4 weeks of 45 or 60 mg AXT914 did not result in the expected changes in circulating bone biomarkers seen with teriparatide. However total serum calcium levels increased above baseline in the 45 and 60 mg AXT914 treatment groups (8.0% and 10.7%, respectively), compared to that in the teriparatide and placebo groups (1.3% and 1.0%, respectively). Thus the trial was terminated after a planned interim analysis due to lack of effect on bone formation biomarkers and dose-limiting effects on serum calcium. In conclusion, AXT914 was well tolerated but the observed transient and reproducible PTH-release after repeat oral administration of AXT914 which showed an exposure profile close to that of s c. PTH, did not translate into a bone anabolic response and was associated with a persistent dose-related increase in serum calcium concentrations.
甲状旁腺中钙敏感受体的拮抗作用会导致甲状旁腺激素（PTH）释放。钙敏感受体拮抗剂是一类旨在利用这一机制的新型分子。为了模拟皮下注射PTH已知的促骨合成代谢药代动力学（PK）特征，此类分子必须引发PTH急剧、短暂且强劲的释放。本文报告了两项关于口服活性钙敏感受体拮抗剂AXT914（一种喹唑啉 - 2 - 酮衍生物）的早期临床研究结果。这些研究符合药品临床试验质量管理规范（GCP），是针对健康志愿者和绝经后女性的PK/PD及耐受性的单剂量和多剂量研究。第一项研究考察了AXT914的单次递增剂量（4至120毫克）和有限的多次剂量（60或120毫克，每日一次，共12天）。第二项研究是一项针对健康绝经后女性的随机、双盲、活性药物与安慰剂对照、为期4周的重复剂量平行组研究（45毫克和60毫克AXT914、安慰剂、20微克福善美/特立帕肽/PTH(1 - 34)片段）。AXT914在所有剂量下耐受性良好，且可重复诱导出所需的PTH释放曲线。然而，4周的45毫克或60毫克AXT914治疗并未导致出现与特立帕肽相同的循环骨生物标志物预期变化。不过，与特立帕肽组和安慰剂组相比（分别为1.3%和1.0%），45毫克和60毫克AXT914治疗组的血清总钙水平高于基线（分别为8.0%和10.7%）。因此，由于对骨形成生物标志物缺乏效果以及对血清钙有剂量限制作用，该试验在计划的中期分析后终止。总之，AXT914耐受性良好，但重复口服AXT914后观察到的短暂且可重复的PTH释放，其暴露特征与皮下注射PTH相近，却未转化为促骨合成代谢反应，且与血清钙浓度持续的剂量相关增加有关。
