Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, South Korea.
Department of Molecular Medicine, Chonnam National University Medical School, Gwangju, South Korea.
J Anesth. 2019 Jun;33(3):381-389. doi: 10.1007/s00540-019-02641-5. Epub 2019 Apr 11.
Palonosetron is the most recent 5-hydroxytryptamine-3 receptor antagonist, and its fixed dose of 0.075 mg is indicated for the prevention of postoperative nausea and vomiting. This study aimed to examine whether fixed dosing is more appropriate than body size-based dosing through the development of a population pharmacokinetic model and model-based simulations.
Fifty-one adult patients undergoing general anesthesia received single intravenous palonosetron administrations 30 min before the end of surgery. Palonosetron concentrations were measured in blood samples collected at various timepoints within 48 h. A population pharmacokinetic analysis was performed by non-linear mixed-effects modeling, and the area under the curves (AUCs) for fixed dosing and body size-based dosing were simulated.
The pharmacokinetics of palonosetron were best described by the three-compartment model, and lean body weight (LBW) was the most significant covariate for all pharmacokinetic parameters. In a patient with LBW of 40 kg, typical clearance and central volume of distribution were 0.102 L/min and 6.98 L, respectively. In simulations, the overall interindividual variability in AUC (0, 48 h) of fixed dosing was not much higher than that of body size-based dosing. In subgroup analysis, the AUCs (0, 48 h) of fixed dosing were considerably lower in the high-weight subgroup and higher in the low-weight subgroup than the median-weight subgroup. In contrast, LBW-based dosing showed similar AUC distributions among the three subgroups.
LBW-based dosing might be suitable for high-weight patients to avoid possible underdosing. Nevertheless, the current fixed dosing of palonosetron is acceptable for adult patients with normal weight.
帕洛诺司琼是最新的 5-羟色胺 3 受体拮抗剂，其 0.075mg 的固定剂量适用于预防术后恶心和呕吐。本研究旨在通过开发群体药代动力学模型和基于模型的模拟来检验固定剂量是否比基于体表面积的剂量更合适。
51 例接受全身麻醉的成年患者在手术结束前 30 分钟接受单次静脉帕洛诺司琼给药。在 48 小时内的不同时间点采集血样，测定帕洛诺司琼浓度。采用非线性混合效应模型进行群体药代动力学分析，并对固定剂量和基于体表面积的剂量的 AUC 进行模拟。
帕洛诺司琼的药代动力学最好用三房室模型来描述，瘦体重（LBW）是所有药代动力学参数的最重要协变量。在 LBW 为 40kg 的患者中，典型清除率和中央分布容积分别为 0.102L/min 和 6.98L。在模拟中，固定剂量的 AUC（0，48 小时）的总体个体间变异性并不比基于体表面积的剂量高很多。亚组分析显示，固定剂量的 AUC（0，48 小时）在高体重亚组中明显低于中值体重亚组，在低体重亚组中高于中值体重亚组。相比之下，基于 LBW 的剂量在三个亚组中显示出相似的 AUC 分布。
基于 LBW 的剂量可能适合高体重患者以避免可能的剂量不足。然而，目前帕洛诺司琼的固定剂量对于正常体重的成年患者是可以接受的。
