Effect of St John's wort on imatinib mesylate pharmacokinetics

• DOI: 10.1016/j.clpt.2004.06.007
• Publication Date: 2004-10-06T14:44:56Z
• Authors: R FRYE; S FITZGERALD; T LAGATTUTA; M HRUSKA; M EGORIN
• Keywords: Imatinib Mesylate; Chronic myelogenous leukemia

Objective Imatinib is a potent inhibitor of the Bcr-Abl and c-kit tyrosine kinases approved for treatment Philadelphia chromosome–positive chronic myelogenous leukemia gastrointestinal stromal tumors. Because imatinib predominantly metabolized by cytochrome P450 (CYP) 3A4, its pharmacokinetics may be altered when it coadministered with drugs or herbs (eg, St John's wort) that modulate CYP3A4 activity. Thus we examined effects wort on pharmacokinetics. Methods This 2-period, open-label, fixed-sequence study was completed 12 healthy subjects (6 men 6 women) aged between 20 51 years. Each subject received 400 mg orally day 1, (300 3 times daily) days 4 to 17, again 15. Serial blood samples were obtained over 72-hour period after each dose. N-desmethyl-imatinib (CGP 74588) quantified in plasma liquid chromatography–mass spectrometry. Results administration increased clearance 43% (P < .001), from 12.5 ± 3.6 L/h 17.9 5.6 L/h; area under concentration versus time curve (AUC) extrapolated infinity decreased 30%, 34.5 9.5 μg · h/mL 24.2 7.0 .001). half-life (12.8 hours 9.0 hours) maximum (Cmax) (2.2 μg/mL 1.8 μg/mL) also significantly .005). Cmax 285 95 ng/mL 318 during dosing, but AUC 0 72 not altered. Conclusions These data indicate increases clearance. patients taking should avoid wort. Concomitant use enzyme inducers, including wort, necessitate an increase dose maintain clinical effectiveness. Clinical Pharmacology & Therapeutics (2004) 76, 323–329; doi:10.1016/j.clpt.2004.06.007