Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies.
OBJECTIVE
To explore safety, pharmacokinetics, and pharmacodynamics of oral administration of resiquimod, a Toll-like receptor 7 and 8 agonist that induces endogenous interferon-alpha, in subjects with chronic hepatitis C virus infection.


METHODS
Two randomized, double-blind phase IIa studies of resiquimod administered two times per week for 4 weeks. Multicenter study (U.S.): 12 subjects received resiquimod 0.01 mg/kg and 4 received placebo. Single center study (France): 6 subjects received 0.01 mg/kg, 11 received 0.02 mg/kg and 6 received placebo.


RESULTS
Resiquimod 0.01 mg/kg was tolerated; two 0.2 mg/kg subjects discontinued treatment. More subjects reported severe grade adverse events at 0.02 mg/kg; events were consistent with systemic cytokine induction, including fever, headache, shivering, and lymphopenia. Mean maximum serum resiquimod concentrations were 3.82+/-1.47 and 7.55+/-4.17 ng/mL for 0.01 mg/kg and 0.02 mg/kg, respectively. At 0.02 mg/kg, two, three and one subjects had maximal reductions in viral levels of at least 1-, 2- and 3-logs, respectively; reductions were generally transient. Interferon-alpha levels appeared correlated with decreases in viral titer and lymphocyte counts, as well as increase in neutrophil counts.


CONCLUSIONS
Oral administration of resiquimod 0.02 mg/kg transiently reduced viral levels but was associated with adverse effects similar to interferon-alpha.
Pockros
Paul J
PJ
Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA. pockros.paul@scrippshealth.org
Guyader
Dominque
D
Patton
Heather
H
Tong
Myron J
MJ
Wright
Terry
T
McHutchison
John G
JG
Meng
Tze-Chiang
TC
D000284:Administration, Oral; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005334:Fever / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D016898:Interferon-alpha / Q000096:biosynthesis; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology; D012367:RNA, Viral / Q000097:blood; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists; D016896:Treatment Outcome; D019562:Viral Load
D007093:Imidazoles; D016898:Interferon-alpha; D012367:RNA, Viral; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C402365:resiquimod