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

Methods

The study protocol was approved by the Veteran's Administration Western New York Healthcare System's institutional review board, and written informed consent was obtained from each subject before study participation.

All subjects were judged to be healthy as determined by a medical history, complete physical examination, and laboratory tests. Each subject was required to be 18-55 years of age, with normal renal and hepatic function. Exclusion criteria were pregnancy or lactation (in women), a history of drug or alcohol abuse, use of any investigational agents within 30 days of enrollment in the study, and use of any prescription or nonprescription drugs or supplements known to interact with CYP3A4 metabolism.

This 18-day, open-label, complete crossover, fixed-sequence, pharmacokinetic study evaluated the pharmacokinetics of a single oral dose of imatinib, either when administered alone or after 2 weeks of treatment with St. John's wort (HBC Inc., Los Angeles, CA). After an overnight fast, subjects received imatinib mesylate 400 mg with a standardized low-fat meal. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after dosing. Plasma was harvested immediately after each sample was collected, and was stored at -70°C until analysis.

After collection of the 48-hour blood sample, treatment with St. John's wort 300 mg 3 times/day was started. After 2 weeks, subjects again received a single oral dose of imatinib mesylate 400 mg with a standardized low-fat meal after an overnight fast. Blood collection and processing were the same as earlier in the study. Subjects were contacted periodically to assess adverse effects and compliance with the St. John's wort regimen, and each subject completed a dosing diary.

Plasma concentrations of imatinib were determined by a validated liquid chromatography with tandem mass spectrometry detection (LC-MS-MS) assay (Perkin Elmer SciEx API 3000; Perkin Elmer, Wellesley, MA) with a heated nebulizer interface. The assay was based on a previously described method, adapted to suit our instrumentation.[11] The column used was the 3.5-µm Symmetry Shield TM RP8, 4.6 x 50 mm (Waters Corp., Milford, MA) with a 1-ml/minute flow rate. The assay uses D8-STI571 (Novartis Pharmaceuticals) as an internal standard. Free (unbound) concentrations of imatinib were also determined for all 3- and 24-hour samples by plasma ultrafiltration at 37°C (Centrifree; Amicon, Inc., Beverly, MA) before assay. The LC-MS-MS assay had a lower and upper limit of quantitation of 2 and 3000 ng/ml, respectively. The interday and intraday coefficient of variation were both less than 5%.

Pharmacokinetic parameters were determined by standard noncompartmental methods (WinNonlin 3.3; Pharsight Corp., Cary, NC). The pharmacokinetic parameters for imatinib administered alone versus with St. John's wort were compared by using a paired t test on logarithmically transformed data (SYSTAT 10.0; SPSS Inc., Chicago, IL). A logarithmic transformation was empirically utilized to better approximate a Gaussian distribution function, an underlying assumption of the paired t test.

For the purpose of these statistical analyses, it was assumed that there were no period effects and that 14 days was an adequate washout period between experiments. Bioequivalence of the area under the conentration-time curve (AUC) and maximum observed concentration (Cmax) was evaluated between the two study periods (taking imatinib alone or with St. John's wort) by using 90% confidence intervals of the geometric mean ratios, equivalent to the two one-sided test.[12] In accordance with standard Food and Drug Administration (FDA) guidelines, the 90% confidence intervals of the geometric mean ratios were required to fall between 0.8 and 1.25 in order to declare bioequivalence. Sample-size calculations were performed to have sufficient power to detect a 40% change in AUC for imatinib in the presence or absence of St. John's wort, with use of a paired t test and an intersubject coefficient of variation of 40% (α=0.05, β=0.8). It was determined that 10 subjects would be required to detect a 40% change in AUC. A p value of 0.05 or less was considered to indicate a statistically significant difference.

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