Abstract 761: Phase I interaction study of docetaxel with supplementation of St. John's wort

Abstract

Abstract Introduction St. John's wort (SJW, Hypericum perforatum) is a herbal antidepressant, which is often used by cancer patients. In healthy volunteers, SJW has previously been shown to induce hepatic CYP3A4 using the selective CYP3A4 substrate midazolam (Wang et al., 2001). In cancer patients, CYP3A4 induction by SJW could result in a decreased exposure to anticancer drugs metabolized by CYP3A4 (e.g. docetaxel), possibly resulting in a decreased therapeutic effect. Induction of docetaxel metabolism by the SJW constituent hyperforin has already been established in vitro (Komoroski et al., 2005). This pharmacokinetic interaction, however, has never been studied before in a clinical setting. Therefore, the aim of this study was to assess the effects of SJW on the pharmacokinetics of docetaxel in cancer patients. Methods In a one-sequence crossover study performed at the Netherlands Cancer Institute and approved by the Institute's Medical Ethical Committee, ten cancer patients received two cycles of docetaxel (135 mg, 60 min IV infusion). Seven days after cycle 1 (docetaxel alone), a commercial SJW extract in a recommended dose of one tablet (containing 300 mg SJW extract) three times daily was supplemented for fourteen days. After this supplementation period, cycle 2 of docetaxel was administered. During cycle 1 and cycle 2, blood samples were collected from 0-48 h after the start of the docetaxel infusion for pharmacokinetic analysis of docetaxel. Docetaxel plasma concentrations were determined by a validated LC-MS/MS assay (Kuppens et al., 2005). The pharmacokinetic endpoint for docetaxel was the area under the plasma concentration-time curve from time 0 to 48 h (AUC0-48), reflecting systemic exposure to docetaxel. By comparing the AUC0-48 of docetaxel in cycle 1 and 2, the effect of SJW on docetaxel pharmacokinetics was determined. Statistical analysis was performed with a paired Student's t test (α = 0.05). Differences in AUC0-48 between cycle 1 and 2 were considered clinically relevant if the 90% CI of the geometric mean ratio was not completely within no-effect limits of 0.80-1.25. Results (preliminary) In eight evaluable patients, supplementation of SJW decreased the mean docetaxel AUC0-48 from 2745 ± 650 to 2364 ± 483 ng/mL*h (p = 0.048, geometric mean ratio 0.86 (90% CI: 0.81-0.92)). Conclusion In this study, the observed decrease of docetaxel AUC0-48 after SJW administration was statistically significant, possibly even clinically relevant. This result indicates that concomitant use of the present SJW formulation in the recommended dose may decrease the therapeutic efficacy of docetaxel and presumably also other anticancer drugs primarily metabolized by CYP3A4. Acknowledgements This study was supported by the Dutch Cancer Society grant UU 2007-3795. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 761. doi:1538-7445.AM2012-761