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Cutaneous Pharmacodynamics of a Toll‐Like Receptor 7 Agonist, 852A, in Humans
Author(s) -
Astry Calvin,
Birmachu Woubalem,
Harrison Lester I.,
Meng TzeChiang
Publication year - 2008
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270008314466
Subject(s) - pharmacodynamics , agonist , medicine , partial agonist , stimulation , receptor , pharmacology , tlr7 , toll like receptor , pharmacokinetics , adverse effect , gastroenterology , immunology , innate immune system
852A is a specific toll‐like receptor 7 (TLR7) agonist. Thirty‐two healthy adults (8 subjects per group) received two 1‐g topical applications over 400 cm 2 , separated by ≥5 days, of 852A 0.01% followed by vehicle, vehicle followed by 852A 0.1%, 852A 0.3% followed by vehicle, or vehicle followed by 852A 1.0%. Systemic absorption was minimal as 852A was not quantifiable in any serum sample up to 24 hours postadministration and was only quantifiable at 24 hours in the urine of 4 of 8 subjects after application of 852A 1.0%. No systemic adverse events were associated with drug treatment. Gene expression analysis from application site biopsies showed a ≥2‐fold increase in expression for 40 genes in at least 2 subjects. CXCL9/MIG (8/32 subjects), CCL2/MCP1 (7/32), and OAS3 (5/32) were most frequently increased, followed by other type I interferon‐inducible genes. Cluster analysis of the genes with a ≥2‐fold increase did not reveal a definitive pattern with respect to 852A concentration or time of biopsy. Overall, single topical application of 852A up to 1.0% was well tolerated. Data gathered from these subjects are suggestive that 852A can produce increases in local gene expression consistent with TLR7 stimulation.