Tegenge Million A, Von Tungeln Linda S, Mitkus Robert J, Anderson Steven A, Vanlandingham Michelle M, Forshee Richard A, Beland Frederick A
Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, FDA, USA.
Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, USA.
Regul Toxicol Pharmacol. 2016 Nov;81:113-119. doi: 10.1016/j.yrtph.2016.08.003. Epub 2016 Aug 4.
Squalene is a component of oil-in-water emulsion adjuvants developed for potential use in some influenza vaccines. The biodistribution of the squalene-containing emulsion adjuvant (AddaVax™) alone and as part of complete H5N1 vaccine was quantified in mechanistically and toxicologically relevant target tissues up to 336 h (14 days) following injection into quadriceps muscle. At 1 h, about 55% of the intramuscularly injected dose of squalene was detected in the local quadriceps muscles and this decreased to 26% at 48 h. Twenty-four hours after the injection, approximately 5%, 1%, and 0.6% of the injected dose was detected in inguinal fat, draining lymph nodes, and sciatic nerve, respectively. The peak concentration for kidney, brain, spinal cord, bone marrow, and spleen was each less than 1% of the injected dose, and H5N1 antigen did not significantly alter the biodistribution of squalene to these tissues. The area-under-blood-concentration curve (AUC) and peak blood concentration (Cmax) of squalene were slightly higher (20-25%) in the presence of H5N1 antigen. A population pharmacokinetic model-based statistical analysis identified body weight and H5N1 antigen as covariates influencing the clearance of squalene. The results contribute to the body of knowledge informing benefit-risk analyses of squalene-containing emulsion vaccine adjuvants.
角鲨烯是一种水包油乳剂佐剂的成分，该佐剂已被开发用于某些流感疫苗。在将含角鲨烯的乳剂佐剂（AddaVax™）单独注射以及作为完整H5N1疫苗的一部分注射到股四头肌后，在长达336小时（14天）的时间内，对机械和毒理学相关靶组织中的角鲨烯生物分布进行了定量分析。注射1小时后，在局部股四头肌中检测到约55%的肌肉注射角鲨烯剂量，48小时时降至26%。注射24小时后，分别在腹股沟脂肪、引流淋巴结和坐骨神经中检测到约5%、1%和0.6%的注射剂量。肾脏、大脑、脊髓、骨髓和脾脏中的峰值浓度均低于注射剂量的1%，H5N1抗原并未显著改变角鲨烯在这些组织中的生物分布。在存在H5N1抗原的情况下，角鲨烯的血药浓度曲线下面积（AUC）和血药峰值浓度（Cmax）略高（20 - 25%）。基于群体药代动力学模型的统计分析确定体重和H5N1抗原为影响角鲨烯清除率的协变量。这些结果有助于丰富有关含角鲨烯乳剂疫苗佐剂的获益-风险分析的知识体系。
