Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, New York, 14260, USA.
Biopharm Drug Dispos. 2011 Nov;32(8):471-81. doi: 10.1002/bdd.770. Epub 2011 Sep 22.
This study aims to characterize the pharmacodynamic properties of denosumab, a RANK ligand inhibitor, and ibandronate, a bisphosphonate, using an integrated bone homeostasis model in postmenopausal women. Mean temporal profiles of denosumab, serum and urine N-telopeptide (sNTX, uNTX), lumbar spine bone mineral density (BMD) following denosumab administration, and urine C-telopeptide (uCTX) and lumbar spine BMD upon ibandronate administration were extracted from the literature. A mechanistic model was developed that integrates denosumab pharmacokinetics with binding to RANK ligand and ibandronate inhibition of osteoclast precursor differentiation to active osteoclasts (AOC). Biomarker concentrations were linked to the AOC pool. The BMD was characterized by a turnover model with stimulation of bone formation and degradation by AOB (active osteoblasts) and AOC pools. The estimated basal sNTX, uNTX and uCTX concentrations were 7.24 nm, 14.4 nmol/mmolCr and 31µg/mmolCr. The BMD degradation rate was 0.00161 day(-1) with stimulation constants associated with AOB and AOC of 1214 and 790 pm(-1) . The plasma ibandronate concentration producing 50% of maximum inhibition of osteoclast differentiation was 522 ng/l. The integrated model, which incorporates multiple pathways of therapeutic intervention, quantitatively describes changes in clinical biomarkers of bone turnover and BMD after denosumab and ibandronate exposures in postmenopausal women.
本研究旨在利用绝经后妇女的综合骨稳态模型来描述 denosumab（一种 RANK 配体抑制剂）和 ibandronate（一种双膦酸盐）的药效学特性。从文献中提取 denosumab 给药后血清和尿 N 端肽（sNTX、uNTX）、腰椎骨密度（BMD）、ibandronate 给药后尿 C 端肽（uCTX）和腰椎 BMD 的平均时间进程。建立了一个机制模型，该模型将 denosumab 药代动力学与与 RANK 配体结合以及 ibandronate 抑制破骨细胞前体向活性破骨细胞（AOC）分化进行整合。生物标志物浓度与 AOC 池相关联。BMD 由 AOB（活性成骨细胞）和 AOC 池刺激骨形成和降解的转换模型来描述。估计的基础 sNTX、uNTX 和 uCTX 浓度分别为 7.24nm、14.4nmol/mmolCr 和 31µg/mmolCr。BMD 降解率为 0.00161 天(-1)，与 AOB 和 AOC 相关的刺激常数分别为 1214 和 790 pm(-1)。抑制 50%破骨细胞分化的血浆 ibandronate 浓度为 522ng/l。该综合模型纳入了多种治疗干预途径，定量描述了绝经后妇女接受 denosumab 和 ibandronate 暴露后骨转换和 BMD 的临床生物标志物的变化。
