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.
Hawke
Roy L
RL
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
Schrieber
Sarah J
SJ
Soule
Tedi A
TA
Wen
Zhiming
Z
Smith
Philip C
PC
Reddy
K Rajender
KR
Wahed
Abdus S
AS
Belle
Steven H
SH
Afdhal
Nezam H
NH
Navarro
Victor J
VJ
Berman
Josh
J
Liu
Qi-Ying
QY
Doo
Edward
E
Fried
Michael W
MW
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