Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C.
Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.
Clinical Assistant Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, CB #7360, Kerr Hall Rm 3310, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA. rhawke@email.unc.edu
Roy L
RL
Hawke
Sarah J
SJ
Schrieber
Tedi A
TA
Soule
Zhiming
Z
Wen
Philip C
PC
Smith
K Rajender
KR
Reddy
Abdus S
AS
Wahed
Steven H
SH
Belle
Nezam H
NH
Afdhal
Victor J
VJ
Navarro
Josh
J
Berman
Qi-Ying
QY
Liu
Edward
E
Doo
Michael W
MW
Fried
D000284:Administration, Oral; D000328:Adult; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D012838:Silymarin / Q000008:administration & dosage*
D012367:RNA, Viral; D012838:Silymarin