Schering-Plough Research Institute, a Division of MSD, Newhouse, Scotland, UK.
Clin Drug Investig. 2011;31(2):101-11. doi: 10.2165/11584730-000000000-00000.
Sugammadex is a γ-cyclodextrin that binds with high affinity to the neuromuscular blocking agents (NMBAs) rocuronium (bromide) and vecuronium (bromide) by encapsulation. Cyclodextrins are known to form inclusion complexes with other compounds.
We utilized a previously developed pharmacokinetic-pharmacodynamic model to identify potential clinically relevant displacement interactions with sugammadex. The potential for sugammadex to capture other drug molecules, thereby reducing their efficacy, is not discussed here.
Isothermal titration calorimetry (ITC) was used to determine the binding affinity (estimated by association rate constant [k(ass)]) between sugammadex and 300 commonly prescribed drugs. The screening included drugs commonly used in or shortly after anaesthesia, commonly prescribed drugs such as antidepressants and cardiovascular drugs, drugs (both steroidal and nonsteroidal) acting on steroidal receptors (such as the corticosteroids hydrocortisone, prednisolone and dexamethasone), and the selective estrogen receptor modulator toremifene. The model took into account the population pharmacokinetic-pharmacodynamic relationships of sugammadex, rocuronium and vecuronium, the binding affinities of the NMBAs and other compounds as determined by ITC, and the relationship between the free concentration of NMBA with sugammadex in the presence of a third complexed compound. Using the model, the critical concentrations of a concomitantly administered compound required to result in a train-of-four (TOF) ratio of <0.9, indicating reoccurrence of neuromuscular blockade, for each plasma concentration of sugammadex and NMBA were calculated. For compounds with a k(ass) value of ≥ 2.5 × 104 mol/L likely to be administered during sugammadex reversal, the combinations of k(ass) and maximum plasma drug concentration (C(max)) were entered into a graph, consisting of a critical line established using a conservative approach, and those compounds above this critical line potentially resulting in a TOF ratio <0.9 were subsequently identified. Clinical validation was performed in a post hoc analysis of data from ten sugammadex studies, in which the impact of various drugs administered perioperatively on neuromuscular recovery was assessed for up to 1 hour after sugammadex administration.
ITC analysis demonstrated that the binding affinity of rocuronium and vecuronium for sugammadex was very high, with k(ass) values of 1.79 × 107 mol/L and 5.72 × 106 mol/L, respectively. Only three compounds (flucloxacillin, fusidic acid and toremifene) were found to have critical combinations of k(ass) and C(max), and thus the potential for displacement. Sugammadex was administered to 600 patients for reversal of rocuronium- or vecuronium-induced blockade in the ten analysed studies, in which 21 co-administered drugs were selected for analysis. No reoccurrence of blockade occurred in any patient.
Of 300 drugs screened, only three (flucloxacillin, fusidic acid and toremifene) were found to have potential for a displacement interaction with sugammadex, which might potentially be noticed as a delay in recovery of the TOF ratio to 0.9. A clinical study found no evidence of a clinically relevant displacement interaction of flucloxacillin with sugammadex; these findings confirm the highly conservative nature of the modelling and simulation assumptions in the present study.
Sugammadex 是一种 γ-环糊精，通过包合作用与神经肌肉阻断剂（NMBA）罗库溴铵（溴化物）和维库溴铵（溴化物）高亲和力结合。环糊精已知与其他化合物形成包合复合物。
我们利用先前开发的药代动力学 - 药效学模型来识别与 sugammadex 可能存在的临床相关置换相互作用。本文不讨论 sugammadex 捕获其他药物分子从而降低其疗效的潜力。
等温滴定量热法（ITC）用于确定 sugammadex 与 300 种常用处方药物之间的结合亲和力（通过缔合速率常数 [k(ass)] 估计）。筛选包括麻醉期间或之后常用的药物、常用的抗抑郁药和心血管药物等常用药物、作用于甾体受体的药物（如皮质醇氢化可的松、泼尼松龙和地塞米松）以及选择性雌激素受体调节剂托瑞米芬。该模型考虑了 sugammadex、罗库溴铵和维库溴铵的群体药代动力学 - 药效学关系、NMBA 和其他化合物的 ITC 测定的结合亲和力，以及 NMBA 与 sugammadex 之间在存在第三种复合物时的游离浓度关系。使用该模型，计算了在 sugammadex 逆转期间同时给予的化合物的临界浓度，以使四成肌收缩比（TOF）比<0.9，表明神经肌肉阻滞再次发生，对于每个 sugammadex 和 NMBA 的血浆浓度。对于 k(ass) 值≥2.5×104 mol/L 的化合物，极有可能在 sugammadex 逆转期间给予，将 k(ass)和最大血浆药物浓度（C(max)）的组合输入到图形中，该图形包含使用保守方法建立的临界线，随后识别出超过该临界线的化合物，可能导致 TOF 比<0.9。在 sugammadex 给药后 1 小时内评估围手术期给予的各种药物对神经肌肉恢复的影响的十项 sugammadex 研究的事后分析中进行了临床验证。
ITC 分析表明，罗库溴铵和维库溴铵与 sugammadex 的结合亲和力非常高，k(ass) 值分别为 1.79×107 mol/L 和 5.72×106 mol/L。只有三种化合物（氟氯西林、夫西地酸和托瑞米芬）被发现具有 k(ass)和 C(max)的临界组合，因此具有置换的潜力。在十项分析研究中，600 名患者接受 sugammadex 逆转罗库溴铵或维库溴铵诱导的阻滞，其中选择了 21 种同时给予的药物进行分析。任何患者均未再次出现阻滞。
在筛选的 300 种药物中，只有三种（氟氯西林、夫西地酸和托瑞米芬）被发现与 sugammadex 具有潜在的置换相互作用，这可能会被发现 TOF 比恢复到 0.9 的时间延迟。一项临床研究未发现氟氯西林与 sugammadex 有临床相关的置换相互作用的证据；这些发现证实了本研究中建模和模拟假设的高度保守性质。
