title: Pharmacokinetics and biodistribution of squalene-containing emulsion adjuvant following intramuscular injection of H5N1 influenza vaccine in mice.
abstract: 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.
authors: Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, FDA, USA. Electronic address: million.tegenge@fda.hhs.gov.
authors: Million A
authors: MA
authors: Tegenge
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, USA.
authors: Linda S
authors: LS
authors: Von Tungeln
authors: Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, FDA, USA.
authors: Robert J
authors: RJ
authors: Mitkus
authors: Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, FDA, USA.
authors: Steven A
authors: SA
authors: Anderson
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, USA.
authors: Michelle M
authors: MM
authors: Vanlandingham
authors: Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, FDA, USA.
authors: Richard A
authors: RA
authors: Forshee
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, USA.
authors: Frederick A
authors: FA
authors: Beland
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D019540:Area Under Curve; D003198:Computer Simulation; D004655:Emulsions; D005260:Female; D006207:Half-Life; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D007273:Injections, Intramuscular; D008297:Male; D008657:Metabolic Clearance Rate; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011136:Polysorbates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D018570:Risk Assessment; D013185:Squalene / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution; D066007:Toxicokinetics
chemical_list: C000590912:Addavax; D000276:Adjuvants, Immunologic; D004655:Emulsions; D007252:Influenza Vaccines; D011136:Polysorbates; D013185:Squalene
keywords: AS03; Lymphatic delivery; MF59; NONMEM; Pre-pandemic; Safety