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

Results

Ten subjects (seven men) completed the trial. Mean ± SD age and weight were 32.5 ± 10.0 years and 83.6 ± 20.1 kg, respectively. All subjects were serum negative for HIV-1 and HIV-2 antibodies, and all women had negative serum pregnancy tests both before and after receiving study agents. Indinavir and milk thistle were well tolerated. One subject had elevated fasting blood glucose levels on both pharmacokinetic sampling days; however, this subject's fasting blood glucose concentrations were elevated before and after receiving study drug. One subject had an elevated alanine aminotransferase level before receiving study drug that decreased to normal by the end of the study. No other laboratory tests showed clinically significant deviation from normal. One subject reported very mild gastric reflux and another reported an episode of malaise while receiving indinavir. An episode of mild nausea and mild headache was reported by one subject receiving both indinavir and milk thistle. No adverse events were reported while receiving milk thistle alone. One subject took hydrochlorothiazide, one took estradiol and medroxyprogesterone, and three took multivitamins throughout the study.

The final pharmacokinetic model had two compartments, first-order absorption following a lag time, and first-order elimination from the central compartment. Individual pharmacokinetic parameters are shown in Table 1 . Indinavir geometric mean (95% CI) steady-state AUC0-8 when given alone and with silymarin was 20.7 hr mg/L (15.3-28.2 hr mg/L) and 19.4 hr mg/L (15.8-23.6 hr mg/L), respectively (Figure 1). The difference [95% CI] between the geometric mean AUC0-8 for indinavir given alone and with silymarin (1.38 hr mg/L [0.79-1.48 hr mg/L]) was not significant (p=0.64), and changes in AUC0-8 did not follow an apparent trend (Figure 2). The geometric mean [95% CI] difference in Cmax (1.0 mg/L [0.88-1.4 mg/L]) also was not significant (p=0.30).

Effect of silymarin on indinavir exposure. AUC = area under the plasma concentration-time curve (hr mg/L). The median is represented by the horizontal line inside the box, the top and bottom of the box represent the 3rd quartile (75th percentile), and the 1st quartile (25th percentile), respectively. Whiskers are drawn to the minimum and maximum observations, and the cross represents the mean.

Effect of silymarin on within-subject variability of indinavir exposure. AUC = area under the plasma concentration-time curve (hr mg/L). Indinavir AUC was estimated at steady state for indinavir administered alone at visit 1 and at steady state for indinavir administered with milk thistle at visit 2.

Neither the geometric mean ratio [90% CI] of indinavir AUC0-8 (0.93 hr mg/L [0.72-1.2 hr mg/L]) nor the geometric mean ratio [90% CI] of indinavir Cmax (0.89 mg/L [0.72-1.1 mg/L]) met the FDA definition of bioequivalence. This was most likely due to small sample size and intrasubject and intersubject variability in exposure, as this study was not powered to determine bioequivalence.

Milk thistle did not significantly influence indinavir trough concentrations. Geometric mean (95% CI) indinavir Cmins when given alone or with silymarin were 0.340 mg/L (0.232-0.497 mg/L) and 0.232 mg/L (0.129-0.419 mg/L), respectively. When comparing indinavir administered alone versus with silymarin, indinavir geometric mean [95% CI] apparent oral volume of distribution (54.1 mg/L [27.9-104.6 mg/L] vs 58.6 mg/L [40.4-85.6 mg/L]) and half-life (3.1 hrs [1.2-8.5 hrs] vs 3.1 hrs [1.3-7.2 hrs]) were not significantly different.

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