Sáez-Llorens X, Castaño E, Null D, Steichen J, Sánchez P J, Ramilo O, Top F H, Connor E
Department of Pediatrics, Infectious Diseases, Hospital del Niño, University of Panama School of Medicine, Panama City.
Pediatr Infect Dis J. 1998 Sep;17(9):787-91. doi: 10.1097/00006454-199809000-00007.
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains.
To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing.
A Phase I/II multicenter, open label, escalating dose clinical trial. PATIENT POPULATION AND DOSING REGIMEN: Children (n=65) born prematurely at < or =35 weeks of gestation who were < or =6 months of age (n=41) and children with bronchopulmonary dysplasia who were < or =24 months of age (n=24) were enrolled. From 1 to 5 monthly injections were given at doses of 5 mg/kg (n=11), 10 mg/kg (n=6) and 15 mg/kg (n=48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay.
The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 microg/ml (range, 52.3 to 174.0) 2 days after the initial dose of 15 mg/kg and 49.2 microg/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of approximately 70 microg/ml. These concentrations were similar to previously published trough concentrations after i.v. administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI-493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups.
MEDI-493 was safe and well-tolerated. Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 microg/ml (the value associated with 99% reduction of pulmonary RSV in the cotton rat model). These concentrations were similar to those previously reported with i.v. administration of MEDI-493.
呼吸道合胞病毒（RSV）是婴幼儿下呼吸道疾病的主要病因。MEDI-493（帕利珠单抗，Synagis）是一种针对RSV融合蛋白的人源化单克隆IgG1抗体，在体外对RSV A和B毒株具有高度活性。
描述每月肌肉注射MEDI-493在早产儿和支气管肺发育不良儿童中的安全性、耐受性、免疫原性和药代动力学，并将这些数据与先前静脉给药获得的信息进行比较。
一项I/II期多中心、开放标签、剂量递增的临床试验。
纳入妊娠≤35周出生、年龄≤6个月的早产儿（n=41）以及年龄≤24个月的支气管肺发育不良儿童（n=24），共65名儿童。每月注射1至5次，剂量分别为5mg/kg（n=11）、10mg/kg（n=6）和15mg/kg（n=48）。在每次给药前、最后一剂后30天以及第一剂和第二剂后的2、7和14天采集血清，通过酶联免疫吸附测定法测量MEDI-493浓度。
MEDI-493的药代动力学与其他人类IgG1抗体相似。初始剂量15mg/kg后2天，平均血清MEDI-493浓度为91.1μg/ml（范围52.3至174.0），30天时为49.2μg/ml（范围13.5至132.0）。每月15mg/kg给药可维持平均谷浓度约70μg/ml。这些浓度与先前发表的静脉给药后的谷浓度相似。MEDI-493注射耐受性良好。只有三名儿童出现被判定可能与MEDI-493相关的不良事件。十名儿童出现短暂的低滴度抗MEDI-493结合滴度（1:10至1:40），这与特定不良事件模式或MEDI-493浓度改变无关。5mg/kg剂量组有两名患者因RSV住院；高剂量组未发现RSV住院病例。
MEDI-493安全且耐受性良好。每月15mg/kg肌肉注射维持的平均血清谷浓度高于40μg/ml（棉鼠模型中与肺部RSV减少99%相关的值）。这些浓度与先前报道的MEDI-493静脉给药后的浓度相似。
