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Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C.
J Clin Pharmacol. 2010 Apr; 50(4):434-49.JC

Abstract

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.

Authors+Show Affiliations

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.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase I
Comparative Study
Controlled Clinical Trial
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19841158

Citation

Hawke, Roy L., et al. "Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C." Journal of Clinical Pharmacology, vol. 50, no. 4, 2010, pp. 434-49.
Hawke RL, Schrieber SJ, Soule TA, et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol. 2010;50(4):434-49.
Hawke, R. L., Schrieber, S. J., Soule, T. A., Wen, Z., Smith, P. C., Reddy, K. R., Wahed, A. S., Belle, S. H., Afdhal, N. H., Navarro, V. J., Berman, J., Liu, Q. Y., Doo, E., & Fried, M. W. (2010). Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. Journal of Clinical Pharmacology, 50(4), 434-49. https://doi.org/10.1177/0091270009347475
Hawke RL, et al. Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C. J Clin Pharmacol. 2010;50(4):434-49. PubMed PMID: 19841158.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. AU - Hawke,Roy L, AU - Schrieber,Sarah J, AU - Soule,Tedi A, AU - Wen,Zhiming, AU - Smith,Philip C, AU - Reddy,K Rajender, AU - Wahed,Abdus S, AU - Belle,Steven H, AU - Afdhal,Nezam H, AU - Navarro,Victor J, AU - Berman,Josh, AU - Liu,Qi-Ying, AU - Doo,Edward, AU - Fried,Michael W, AU - ,, Y1 - 2009/10/19/ PY - 2009/10/21/entrez PY - 2009/10/21/pubmed PY - 2010/9/30/medline SP - 434 EP - 49 JF - Journal of clinical pharmacology JO - J Clin Pharmacol VL - 50 IS - 4 N2 - 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. SN - 1552-4604 UR - https://www.unboundmedicine.com/medline/citation/19841158/Silymarin_ascending_multiple_oral_dosing_phase_I_study_in_noncirrhotic_patients_with_chronic_hepatitis_C_ L2 - https://doi.org/10.1177/0091270009347475 DB - PRIME DP - Unbound Medicine ER -