The Influence of St. John's Wort on the Pharmacokinetics and Protein Binding of Imatinib Mesylate

Patrick F. Smith, Pharm.D.; Julie M. Bullock, Pharm.D.; Brent M. Booker, Pharm.D.; Curtis E. Haas, Pharm.D.; Charles S. Berenson, M.D.; William J. Jusko, Ph.D.

Disclosures

Pharmacotherapy. 2004;24(11) 

In This Article

Results

Seven men and three women, with a mean ± SD age of 43.7 ± 6.4 and 33.3 ± 6.0 years, respectively, were enrolled in and completed the study. The mean body weight was 80.5 ± 6.0 kg. The treatments were well tolerated, with no adverse events reported during the study.

The pharmacokinetics of imatinib were significantly altered after administration of St. John's wort (Figure 1). Pharmacokinetic parameters are summarized in Table 1 . The median imatinib AUC from time zero to infinity (AUC0- ) was reduced by approximately 32% (28.9 vs 19.7 µg•hr/ml, p=0.0001). This reduction in imatinib exposure appears to be a result of both a decrease in oral absorption and an increase in the rate of elimination, with a 29% reduction in Cmax and a 21% reduction in half-life (p<0.01 for both). The 48-hour concentration (Clast) of imatinib was also significantly reduced by St. John's wort, by approximately 55% (p=0.00002).

Plasma profiles for imatinib at baseline (closed circles) and after administration of St. John's wort (open triangles), with data shown as mean ± standard error.

Figure 2 illustrates the influence of St. John's wort on imatinib AUC0- in each subject. Subjects with higher AUC0- values at baseline were most susceptible to the enzyme-inducing effects of St. John's wort. The four individuals with a baseline AUC0- of greater than 30 µg•hour/ml had a decrease in AUC0- of 41.7%, 40.8%, 39.6%, and 32.2%, respectively. Reductions of only 20.1% and 11.7% in AUC0- were observed in the two individuals who had a baseline of less than 20 µg•hour/ml. Both AUC0- and Cmax failed the bioequivalence test, with the 90% confidence intervals of the geometric mean ratios falling outside of the required 80-125% (56% [range 46-70%] for AUC0- and 76% [range 59-87%] for Cmax).

Area under the plasma concentration-time curve (AUC), maximum observed concentration (Cmax), and half-life for imatinib given alone and after administration of imatinib with St. John's Wort in individual subjects (closed squares). Open circles represent median values.

Imatinib was approximately 95% protein bound in all subjects, with little intersubject variability (mean 94.9 ± 1.4%, range 90.3-97.7%). Protein binding was concentration independent over the range studied (0.12-2.6 µg/ml) and was not altered by St. John's wort. These protein-binding results are similar to the values reported in imatinib's product labeling.[13]

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