Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, 1401 Rockville Pike, Rockville, MD, 20852, USA,
J Pharmacokinet Pharmacodyn. 2013 Oct;40(5):545-56. doi: 10.1007/s10928-013-9328-y. Epub 2013 Aug 4.
Squalene is used in the oil phase of certain emulsion vaccine adjuvants, but its fate as a vaccine component following intramuscular (IM) injection in humans is unknown. In this study, we constructed a physiologically-based pharmacokinetic (PBPK) model for intramuscularly injected squalene-in-water (SQ/W) emulsion, in order to make a quantitative estimation of the tissue distribution of squalene following a single IM injection in humans. The PBPK model incorporates relevant physicochemical properties of squalene; estimates of the time course of cracking of a SQ/W emulsion; anatomical and physiological parameters at the injection site and beyond; and local, preferential lymphatic transport. The model predicts that a single dose of SQ/W emulsion will be removed from human deltoid muscle within six days following IM injection. The major proportion of the injected squalene will be distributed to draining lymph nodes and adipose tissues. The model indicates slow decay from the latter compartment most likely due to partitioning into neutral lipids and a low rate of squalene biotransformation there. Parallel pharmacokinetic modeling for mouse muscle suggests that the kinetics of SQ/W emulsion correspond to the immunodynamic time course of a commercial squalene-containing adjuvant reported in that species. In conclusion, this study makes important pharmacokinetic predictions of the fate of a squalene-containing emulsion in humans. The results of this study may be relevant for understanding the immunodynamics of this new class of vaccine adjuvants and may be useful in future quantitative risk analyses that incorporate mode-of-action data.
角鲨烯被用于某些乳剂疫苗佐剂的油相中，但它在人类肌肉内注射（IM）后作为疫苗成分的命运尚不清楚。在这项研究中，我们构建了角鲨烯水包油（SQ/W）乳剂肌内注射的生理基于药代动力学（PBPK）模型，以便对人类单次 IM 注射后角鲨烯的组织分布进行定量估计。该 PBPK 模型纳入了角鲨烯的相关物理化学性质；角鲨烯 W/O 乳剂破裂的时间过程估算；注射部位及以外的解剖学和生理学参数；以及局部优先淋巴转运。该模型预测，单次 SQ/W 乳剂剂量将在 IM 注射后六天内从人类三角肌中清除。注入的角鲨烯的主要部分将分布到引流淋巴结和脂肪组织。该模型表明，来自后者的角鲨烯缓慢衰减，很可能是由于分配到中性脂质中，以及那里的角鲨烯生物转化率低。对小鼠肌肉的平行药代动力学模型表明，SQ/W 乳剂的动力学与该物种中报道的含有角鲨烯的佐剂的免疫动力学时间过程相对应。总之，本研究对角鲨烯乳剂在人类中的命运进行了重要的药代动力学预测。本研究的结果可能有助于理解这种新型疫苗佐剂的免疫动力学，并且在包含作用模式数据的未来定量风险分析中可能有用。
