Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

Hawke, Roy L. PharmD, PhD
Schrieber, Sarah J. PharmD
Soule, Tedi A. PharmD
Wen, Zhiming PhD
Smith, Philip C. PhD
Reddy, Rajender K. MD
Wahed, Abdus S. PhD
Belle, Steven H. PhD
Afdhal, Nezam H. MD
Navarro, Victor J. MD
Berman, Josh MD, PhD, FAAP
Liu, Qi-Ying MD
Doo, Edward MD
Fried, Michael W. MD

From the Division of Pharmacotherapy & Experimental Therapeutics (Dr Hawke, Dr Schrieber, Dr Soule) and Division of Molecular Pharmaceutics (Dr Wen, Dr Smith), UNC Eshelman School of Pharmacy, and Division of Gastroenterology and Hepatology, School of Medicine (Dr Fried), University of North Carolina, Chapel Hill, North Carolina; Division of Gastroenterology, University of Pennsylvania (Dr Reddy); Department of Biostatistics (Dr Wahed) and Department of Epidemiology (Dr Belle), University of Pittsburgh, Pittsburgh, Pennsylvania; Liver Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Dr Afdhal); Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, Pennsylvania (Dr Navarro); National Center for Complementary and Alternative Medicine (Dr Berman, Dr Liu) and Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (Dr Doo), National Institutes of Health, Bethesda, Maryland. Submitted for publication March 25, 2009; revised version accepted July 27, 2009. Address for correspondence: Roy L. Hawke, PharmD, PhD, Clinical Assistant Professor, 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; e-mail: [email protected].

The Journal of Clinical Pharmacology 50(4):p 434-449, April 2010. | DOI: 10.1177/0091270009347475

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.