Coadministration of Milk Thistle and Indinavir in Healthy Subjects

Robert DiCenzo, Pharm.D., Mark Shelton, Pharm.D., Kelly Jordan, Pharm.D., Christine Koval, M.D., Alan Forrest, Pharm.D., Richard Reichman, M.D., Gene Morse, Pharm.D.

Disclosures

Pharmacotherapy. 2003;23(7) 

In This Article

Methods

This sequential, crossover trial was conducted in healthy men and women not of childbearing potential (bilateral tubal ligation, hysterectomy, menopause) between 18 and 55 years of age who had a negative HIV test, normal clinical laboratory blood tests, and normal physical examination. Exclusion criteria were smoking in the past year, ingestion of milk thistle within 30 days, use of agents known to influence CYP450, use of herbal supplements, and active or history of liver disease.

All outpatient and inpatient procedures were performed in the General Clinical Research Center (GCRC) at the University of Rochester Medical Center. Subjects received indinavir (Crixivan; Merck & Co., Inc., Whitehouse Station, NJ) 800 mg at 8 A.M., 4 P.M., and midnight on day 1. The first dose was administered in the GCRC and subjects reported back to the center that evening for the first of two overnight stays. On day 2 subjects received indinavir 800 mg in the fasted state (no food within 8 hours) at 8 A.M.; plasma samples were drawn -0.25, 0.5, 1, 2, 3, 4, and 5 hours after this dose. Subjects received a standard breakfast consisting of 4 ounces of skim milk, 3/4 ounce of corn flakes, and 4 g of sugar 1 hour after the morning dose and were discharged after the last blood draw. They were instructed not to drink alcohol or citrus beverages on days 1, 2, 16, and 17. On day 3 subjects began taking silymarin 160 mg (standardized milk thistle; General Nutrition Corp., Pittsburgh, PA) 3 times/day. On day 16 they began taking indinavir with silymarin in the same dosages, and returned to the GCRC in the evening for their second overnight stay. On day 17 subjects took their last doses of silymarin 160 mg and indinavir 800 mg. Plasma sampling times and meals were identical to those for day 2. After the last blood draw on day 17 subjects were discharged from the GCRC. They returned to the center between days 42 and 56 for a physical examination, when blood was drawn for clinical laboratory tests and an HIV test.

Each blood sample was centrifuged for 10 minutes at 800 x g. Plasma was separated into three aliquots and stored at -70°C until shipped to the University at Buffalo Adult AIDS Clinical Trials Group Pharmacology Support Laboratory, Buffalo, NY. Indinavir plasma concentrations were quantified by a validated high-performance liquid chromatography (HPLC) assay with ultraviolet detection. Indinavir interassay coefficients of variation (CVs) were 3.2% at 75 ng/ml and 2.8% at 3500 ng/ml, and intraassay CVs were 1.7-8.5% at 75 ng/ml and 0.3-3.4% at 3500 ng/ml. Lower limit of quantification for the assay was 12.5 ng/ml.

Before subject enrollment, 10 milk thistle capsules were assayed for silymarin content by a validated HPLC method (Research Triangle Laboratories, Inc., Raleigh, NC). The amount of silymarin was 173 mg/capsule, and all milk thistle dispensed during this study was from the same lot number.

Indinavir plasma concentrations were first modeled in Adapt II using maximum likelihood.[10,11] For all modeling methods, observed data were weighted by the inverse of the fitted variance. The variance model assumed a linear relationship between standard deviation and fitted concentration. Model discrimination was performed using Akaike's information criterion. Once the structural model was developed, final pharmacokinetic estimates were calculated by a MAP Bayesian approach using iterative two-stage analysis. Indinavir concentrations 8 hours after dose administration (Cmin) were computed as the fitted Cmin 8 hours after the dose. Maximum concentration during the dosing interval (Cmax) was determined by visual inspection. Ten subjects were required to have 80% power to detect a 50% difference in indinavir area under the plasma concentration-time curve (AUC0-8) using a two-sided paired t test with an a error of 0.05 assuming a 40% CV.[12] Confidence intervals (CIs) were constructed on results of analyses of variance of each pharmacokinetic parameter or its log transform. Bioequivalence was defined as the 90% CI of the geometric mean ratio of AUC0-8 or Cmax being within Food and Drug Administration (FDA) guidelines (0.80-1.25). All statistical analyses were conducted using SAS system, version 8 (SAS Institute, Cary, NC).

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