The Effect of St John's Wort on the Pharmacokinetics of Docetaxel
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Clin Pharmacokinet (2014) 53:103–110 DOI 10.1007/s40262-013-0102-5 ORIGINAL RESEARCH ARTICLE The Effect of St John’s Wort on the Pharmacokinetics of Docetaxel Andrew K. L. Goey • Irma Meijerman • Hilde Rosing • Serena Marchetti • Marja Mergui-Roelvink • Marianne Keessen • Jacobus A. Burgers • Jos H. Beijnen • Jan H. M. Schellens Published online: 26 September 2013 Ó Springer International Publishing Switzerland 2013 Abstract 14 days of supplementation with SJW (300 mg extract Background and Objective St John’s wort (SJW), a her- [HyperiplantÒ] three times daily). bal antidepressant, is commonly used by cancer patients, Results SJW supplementation resulted in a statistically and its component hyperforin is a known inducer of the significant decrease in the mean area under the docetaxel cytochrome P450 (CYP) isoenzyme 3A4. Here, the plasma concentration–time curve extrapolated to infinity potential pharmacokinetic interaction between SJW and the (AUC?) from 3,035 ± 756 to 2,682 ± 717 ng Á h/mL sensitive CYP3A4 substrate docetaxel was investigated. (P = 0.045). Furthermore, docetaxel clearance signifi- Methods In ten evaluable cancer patients, the pharma- cantly increased from 47.2 to 53.7 L/h (P = 0.045) after cokinetics of docetaxel (135 mg administered intrave- SJW intake. The maximum plasma concentration and nously over 60 min) were compared before and after elimination half-life of docetaxel were (non-significantly) decreased after SJW supplementation. In addition, the incidence of docetaxel-related toxicities was lower after SJW supplementation. A. K. L. Goey (&) Á J. H. Beijnen Á J. H. M. Schellens Division of Pharmacoepidemiology and Clinical Pharmacology, Conclusion These results suggest that concomitant use of Department of Pharmaceutical Sciences, Utrecht University, docetaxel and the applied SJW product should be avoided Utrecht, The Netherlands to prevent potential undertreatment of cancer patients. e-mail: [email protected] Present Address: A. K. L. Goey 1 Introduction Clinical Pharmacology Program, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA The herbal antidepressant St John’s wort (SJW; Hypericum I. Meijerman perforatum) is one of the top-selling herbal supplements in Division of Pharmacology, Department of Pharmaceutical the USA and Europe [1, 2]. The popularity of SJW among Sciences, Utrecht University, Utrecht, The Netherlands cancer patients is reflected by its ranking in the top eight alternative medicines [3]. H. Rosing Á J. H. Beijnen Department of Pharmacy and Pharmacology, Slotervaart To date, SJW has been known to cause many pharma- Hospital/The Netherlands Cancer Institute, Amsterdam, cokinetic herb–drug interactions [4]. The SJW constituent The Netherlands hyperforin is a well-known activator of the pregnane X receptor (PXR) [5], which results in increased transcription S. Marchetti Á M. Mergui-Roelvink Á M. Keessen Á J. H. M. Schellens of the cytochrome P450 3A4 isoenzyme (CYP3A4) and the Department of Clinical Pharmacology, The Netherlands Cancer drug efflux transporter ABCB1 (P-glycoprotein). Conse- Institute, Amsterdam, The Netherlands quently, induction of CYP3A4 and/or ABCB1 increases the metabolism and excretion of drug substrates, eventually J. A. Burgers Department of Thoracic Oncology, The Netherlands Cancer leading to decreased systemic exposure and possibly also Institute, Amsterdam, The Netherlands to decreased therapeutic efficacy. 104 A. K. L. Goey et al. As CYP3A4 is involved in the metabolism of many criteria were alcoholism; drug addiction; psychotic disor- anticancer drugs (e.g. docetaxel, paclitaxel, imatinib, iri- ders leading to non-adequate follow-up; concomitant use of notecan), concomitant use of SJW may have serious clin- multidrug resistance (MDR)- and CYP3A-modulating ical consequences, especially undertreatment. In vitro drugs; uncontrolled infectious disease; human immunode- results have already shown that hyperforin increases the ficiency virus (HIV)-1 or -2; unresolved ([grade 1) tox- metabolism of docetaxel [6]. To date, however, no clinical icities from previous chemotherapy; bowel obstruction or studies have been executed to determine the clinical rele- motility disorders that might influence the absorption of vance of this interaction. On the basis of significant clinical drugs; pregnancy; chronic use of H2-receptor antagonists interactions between SJW and the sensitive CYP3A4 sub- or proton pump inhibitors; neurological disease that might strate midazolam [7–12] and the anticancer drugs imatinib render a patient at increased risk of peripheral or central [13, 14] and irinotecan [15], a pharmacokinetic interaction neurotoxicity; and the presence of symptomatic cerebral or study of SJW and docetaxel should also be performed. leptomeningeal metastases. All patients provided written Compared with the metabolism of imatinib and irinotecan, informed consent prior to study entry and were treated in which enzymes and drug transporters other than between May 2010 and October 2011. CYP3A4 are involved [16, 17], docetaxel is more exclu- The study protocol (EudraCT number 2008-000886-41) sively metabolized by CYP3A4 [18] and is thus a good was approved by the Medical Ethical Committee of substrate for studying CYP3A4-mediated pharmacokinetic The Netherlands Cancer Institute (NKI; Amsterdam, interactions. The Netherlands) and was conducted in accordance with Therefore, this clinical study was designed to determine current standards of Good Clinical Practice, the WHO whether there is a significant pharmacokinetic interaction Declaration of Helsinki and the Medical Research Involv- between SJW and docetaxel. The secondary objective was ing Human Subjects Act (WMO). to determine whether the incidence of docetaxel-related toxicities would be affected if a herb–drug interaction 2.2 Study Design and Treatment occurred. This open-label, non-randomized, crossover study was conducted at the NKI. On day 1, docetaxel (TaxotereÒ; 2 Methods Aventis Pharma SA, Antony, France) was administered as an absolute dose of 135 mg (60 min intravenously). The 2.1 Patients dose of 135 mg was based on a safe dose of 75 mg/m2 and an average body surface area of 1.8 m2. From day 7 until Patients with histological or cytological proof of cancer for the morning of day 22, patients received SJW tablets whom treatment with docetaxel was considered to be of (HyperiplantÒ 300 mg dry SJW extract standardized to potential therapeutic benefit—for example, patients with 0.36–0.84 mg hypericin and 9–19 mg hyperforin; VSM advanced breast, gastric, oesophageal, bladder, ovarian, Geneesmiddelen BV, Alkmaar, The Netherlands) at the non-small cell lung, prostate, or head and neck cancer— recommended dose of one tablet three times daily. On the were included. Other inclusion criteria were age morning of day 22, the second cycle of docetaxel was C18 years; performance status B2 according to the World administered according to the same dosing schedule as that Health Organization (WHO) scale; life expectancy used on day 1 (Fig. 1). [3 months; absolute neutrophil count (ANC) C1.5 9 109/ Standard docetaxel pre-treatment consisted of oral L; platelet count C100 9 109/L; haemoglobin level dexamethasone 8 mg twice daily for three consecutive C6.0 mmol/L; impaired hepatic function as defined by days: 1 day before, on the day of docetaxel administration serum bilirubin B1.5 times the upper limit of normal and 1 day after. (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) B2.5 times the ULN; impaired 2.3 Pharmacokinetic Analysis of Docetaxel renal function as defined by serum creatinine B1.5 times the ULN or creatinine clearance C50 mL/min; and ability During the two docetaxel cycles, blood samples were and willingness to swallow and retain oral medication, to collected for pharmacokinetic analysis of docetaxel in comply with the protocol procedures and to follow dietary plasma. Blood samples were drawn at predose and at 0.25, restrictions. 0.5, 0.75, 1, 1.5, 2, 4, 7, 10, 24 and 48 h after the start of Patients were excluded if they had received any treat- the docetaxel infusion. Within 1 h after collection, samples ment with investigational drugs within 30 days before the were centrifuged at 1,500 9 g for 10 min at 4 °C, and start of the study or had used herbal supplements within plasma was isolated and stored at -20 °C until analysis. 6 weeks prior to the study treatment. Other exclusion Docetaxel plasma concentrations were determined using a Effect of St John’s Wort on the Pharmacokinetics of Docetaxel 105 Fig. 1 Study design. On day 1, the first docetaxel cycle was pharmacokinetic (PK) analysis of docetaxel were collected from administered. From day 7 until the morning of day 22, St John’s time 0 until 48 h after the start of the infusion. On days 7, 14 and 22, wort was supplemented, followed by a second cycle of docetaxel on blood samples were collected for hyperforin analysis. IV intravenous day 22. During both docetaxel cycles, blood samples for validated assay based on liquid chromatography coupled plasma samples were protected from ambient light during with tandem mass spectrometry (LC–MS/MS) [19]. In sample preparation. short, in this assay, docetaxel was extracted from the LC was carried out using a Polaris 3 C18-A column matrix using liquid–liquid extraction with tert-butyl methyl (50 mm 9 2 mm ID, particle size 3 lm; Varian, Middel- ether. Paclitaxel was used as the internal standard. Sample burg, The Netherlands) with a Polaris 3 C18-A pre-column injections (25 lL) were made on a C18 column (10 mm 9 2 mm ID, particle size 3 lm; Varian). Further, (150 9 2.1 mm ID, particle size 5 lm) coupled to a guard the LC equipment consisted of a DGU-14A degasser, a column (10 9 2 mm). The mobile phase consisted of CTO-10Avp column oven, a Sil-HTc autosampler and two methanol—10 mM NH4OH (7:3, v/v) which was delivered LC10-ADvp-l pumps (all from Shimadzu, Kyoto, Japan). at a flow rate of 0.2 mL/min. The run time was 7.5 min.