title: A physiologically-based pharmacokinetic (PBPK) model of squalene-containing adjuvant in human vaccines.
abstract: 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.
authors.affiliation: Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, 1401 Rockville Pike, Rockville, MD, 20852, USA, million.tegenge@fda.hhs.gov.
authors.forename: Million A
authors.initials: MA
authors.lastname: Tegenge
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mitkus
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D004655:Emulsions / Q000008:administration & dosage; D006801:Humans; D007273:Injections, Intramuscular / Q000379:methods; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D013185:Squalene / Q000276:immunology* / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000276:immunology; D014612:Vaccines / Q000276:immunology* / Q000493:pharmacokinetics*
chemical_list: D000276:Adjuvants, Immunologic; D004655:Emulsions; D014612:Vaccines; D013185:Squalene
references.citation: J Pharmacol Toxicol Methods. 2012 Mar;65(2):49-57
references.pmid: 22326278
references.citation: J Control Release. 2001 Apr 28;71(3):339-50
references.pmid: 11295226
references.citation: Biochim Biophys Acta. 1982 Aug 18;712(2):374-81
references.pmid: 7126611
references.citation: J Pharm Sci. 2010 Mar;99(3):1582-600
references.pmid: 19774657
references.citation: Immunity. 2010 Oct 29;33(4):530-41
references.pmid: 21029963
references.citation: Vaccine. 2011 Nov 28;29(51):9563-72
references.pmid: 21906648
references.citation: Am J Physiol. 1992 Jun;262(6 Pt 2):R1025-32
references.pmid: 1621856
references.citation: J Immunol. 1994 Nov 1;153(9):4029-39
references.pmid: 7930610
references.citation: Vaccine. 2011 Mar 16;29(13):2461-73
references.pmid: 21256188
references.citation: Lipids. 1983 Mar;18(3):233-8
references.pmid: 6855483
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10501-6
references.pmid: 18650390
references.citation: J Pharmacokinet Pharmacodyn. 2012 Feb;39(1):67-86
references.pmid: 22143261
references.citation: J Lipid Res. 1974 Nov;15(6):563-73
references.pmid: 4430879
references.citation: Adv Drug Deliv Rev. 2001 Aug 23;50(1-2):3-20
references.pmid: 11489331
references.citation: Cell. 2012 Mar 16;148(6):1284-92
references.pmid: 22424235
references.citation: JAMA. 1997 Jun 4;277(21):1709-11
references.pmid: 9169899
references.citation: Clin Cancer Res. 1999 Oct;5(10):2918-24
references.pmid: 10537361
references.citation: Expert Rev Vaccines. 2010 Oct;9(10):1135-41
references.pmid: 20923265
references.citation: Vaccine. 1999 Oct 14;18(5-6):434-9
references.pmid: 10519932
references.citation: Expert Rev Vaccines. 2012 Feb;11(2):145-57
references.pmid: 22309663
references.citation: Therapie. 2010 Nov-Dec;65(6):533-41
references.pmid: 21176760
references.citation: J Lipid Res. 1976 Jan;17(1):38-45
references.pmid: 1255019
references.citation: J Invest Dermatol. 1955 Feb;24(2):125-9
references.pmid: 14354270
references.citation: J Angiogenes Res. 2010 Aug 11;2:14
references.pmid: 20701757
references.citation: Biochem Biophys Res Commun. 2010 Mar 12;393(3):350-5
references.pmid: 20018176
references.citation: Vaccine. 2008 Jun 19;26(26):3209-22
references.pmid: 18462843
references.citation: Eur J Clin Invest. 1979 Oct;9(5):355-62
references.pmid: 118029
references.citation: Vaccine. 2012 Jun 19;30(29):4341-8
references.pmid: 22682289
references.citation: Methods Mol Biol. 2010;626:29-40
references.pmid: 20099119
references.citation: J Biol Chem. 1982 Sep 10;257(17):10300-5
references.pmid: 7107606
references.citation: Expert Rev Vaccines. 2011 Apr;10(4):447-62
references.pmid: 21506643
references.citation: Nat Immunol. 2011 Jun;12(6):509-17
references.pmid: 21739679
references.citation: Pharm Biotechnol. 1995;6:277-96
references.pmid: 7551221
references.citation: Cell Immunol. 1998 May 25;186(1):18-27
references.pmid: 9637761
references.citation: J Immunol. 2012 Apr 1;188(7):3088-98
references.pmid: 22351935
references.citation: Atherosclerosis. 1994 Apr;106(2):169-78
references.pmid: 8060377
references.citation: Expert Opin Biol Ther. 2010 Apr;10(4):639-51
references.pmid: 20218923
references.citation: Expert Rev Vaccines. 2012 Mar;11(3):349-66
references.pmid: 22380826
references.citation: J Immunol Methods. 2006 May 30;312(1-2):12-9
references.pmid: 16624319
references.citation: Clin Pharmacol Ther. 1975 Jan;17(1):44-7
references.pmid: 1122668
references.citation: Toxicol Ind Health. 1997 Jul-Aug;13(4):407-84
references.pmid: 9249929
references.citation: Molecules. 2009 Sep 01;14(9):3286-312
references.pmid: 19783926
references.citation: J Pharm Sci. 1970 Aug;59(8):1088-92
references.pmid: 4989724
references.citation: Physiol Rev. 1994 Jan;74(1):163-219
references.pmid: 8295933
references.citation: Vaccine. 2013 Apr 18;31 Suppl 2:B163-75
references.pmid: 23598478
references.citation: J Pharm Sci. 2012 Jun;101(6):2250-61
references.pmid: 22388869
references.citation: J Clin Invest. 2011 Aug;121(8):3120-32
references.pmid: 21765213
references.citation: Int J Obes. 1981;5(6):613-8
references.pmid: 7319685
references.citation: J Lipid Res. 2001 Jun;42(6):988-94
references.pmid: 11369807