Population Pharmacokinetics of Palivizumab, a Humanized Anti-Respiratory Syncytial Virus Monoclonal Antibody, in Adults and Children
Population Pharmacokinetics of Palivizumab, a Humanized Anti-Respiratory Syncytial Virus Monoclonal Antibody, in Adults and Children
复制标题
DOI：
10.1128/aac.06446-11
复制
发表时间：
2012-09-01
影响因子：
4.9
通讯作者：
Roskos, Lorin K.
中科院分区：
文献类型：
--
作者：
Robbie, Gabriel J.;Zhao, Liang;Roskos, Lorin K.
尽管Palivizumab已经上市十多年了，但关于Palivizumab的药代动力学(PK)和最佳剂量仍然存在困惑。Palivizumab是一种人源化的IgG1 kappa单抗，用于预防呼吸道合胞病毒(RSV)疾病高危儿童患者由呼吸道合胞病毒(RSV)引起的严重下呼吸道疾病。这项分析的目的是利用非线性混合效应模型来描述成人和儿童中帕利维珠单抗的群体PK，量化个体协变量对帕利维珠单抗处置变异性的影响，并比较不同给药方案下的帕利维珠单抗暴露。Palivizumab PK数据来自22个临床研究，用于模型开发。该模型采用两步法建立：(I)肌肉给药后一级吸收的两室模型适用于成人数据，(Ii)相同的结构模型适用于稀疏的儿科数据，使用NONMEM$Premier子程序，从成人分析中获得信息先验。体重和年龄描述符，结合胎龄和出生后年龄(PAGE)，使用渐近指数模型最好地描述儿科患者的Palivizumab清除。Palivizumab清除量从10.2ml/d略增至11.9ml/d，其清除量随PAGE的变化从7个月至18个月不等。协变量分析表明，患有慢性肺病的儿童和抗药抗体效价为80的儿童的清除率高出20%。这些协变量不能很好地解释个体间的差异。在标签显示的儿科人群中，体重是影响帕利维珠单抗PK的主要人口统计学因素。以体重为基础的15毫克/公斤剂量在不同孕期和出生后的儿童中产生相似的帕利维珠单抗浓度。模拟结果表明，正常足月儿和早产儿的palivizumab PK差异不大。模拟还表明，与标签一致的5个月剂量为15 mg/kg的palivizumab，并在两个随机临床试验中进行了研究，与3个月剂量的简化剂量方案相比，提供了更多和更长时间的palivizumab暴露。
Although it has been on the market for over a decade, confusion remains regarding the pharmacokinetics (PK) and optimal dosing of palivizumab, a humanized IgG1 kappa monoclonal antibody indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. The objectives of this analysis were to characterize the population PK of palivizumab in adults and children using nonlinear mixed-effect modeling, quantify the effects of individual covariates on variability in palivizumab disposition, and compare palivizumab exposures for various dosing scenarios. Palivizumab PK data from 22 clinical studies were used for model development. The model was developed using a two-stage approach: (i) a 2-compartment model with first-order absorption after intramuscular administration was fitted to adult data, and (ii) the same structural model was fitted to the sparse pediatric data using the NONMEM $PRIOR subroutine, with informative priors obtained from the adult analysis. Body weight and an age descriptor that combines gestational age and postnatal age (PAGE) using an asymptotic-exponential model best described palivizumab clearance in pediatric patients. Palivizumab clearance increased slightly from 10.2 ml/day to 11.9 ml/day as a function of PAGE ranging from 7 to 18 months. Covariate analysis indicated a 20% higher clearance in children with chronic lung disease and in children with antidrug antibody titer values of >= 80. These covariates did not substantially explain interindividual variability. In the label-indicated pediatric population, body weight was the primary demographic factor affecting palivizumab PK. Body weight-based dosing of 15 mg/kg yields similar palivizumab concentrations in children of different gestational and postnatal ages. Simulations demonstrated that there was little difference in palivizumab PK between healthy term and premature infants. Simulations also demonstrated that the 5 monthly palivizumab doses of 15 mg/kg, consistent with the label and studied in two randomized, clinical trials, provided greater and more prolonged palivizumab exposure than did an abbreviated dosing regimen of 3 monthly doses.