Study on the possible pharmacokinetic interaction between grean tea supplements and tamoxifen in patients with breast cancer. "the TEA study"

Tamoxifen is an effective oral estrogen receptor (ER) antagonist with
relatively mild side-effects for the treatment of ER positive breast cancer.
Nowadays many (cancer) patients often use additional herbs or supplements next
to their anti-cancer therapy. Besides the believed positive effects of these
supplements, the risk of possible severe drug-drug interactions ultimately
leading to diminished therapeutic outcomes or an increase in toxicity is also
increased. One of the most popular supplements used by cancer patients is
green tea. Green tea is believed to have anti-cancer effects due to catechins,
a class of flavonoids that exert potent antioxidant activity, of which
(-)-epigallocatechin-3-gallate (EGCG) has the highest antioxidant potential.

Several in vitro studies suggest inhibition by green tea supplements of several
phase I metabolizing enzymes like CYP3A4 and CYP2D6 and inhibition of several
drug-transporters among which the efflux transporter P-glycoprotein (P-gP) and
several influx-transporters like organic anion transporting polypeptides
(OATP). EGCG significantly increased the bioavailability of several drugs like
verapamil, simvastatin, 5-fluoruracil and diltiazem in rat studies.

After absorption tamoxifen is metabolized mainly by CYP3A4 and CYP2D6 in
several (active) metabolites of which endoxifen is the most important.
Tamoxifen, like many anti-cancer drugs, relies on phase II metabolism before
they can be excreted from the body. Endoxifen is ultimately glucuronidated into
endoxifen-glucuronide mainly by UGT1A8 and UGT1A10. Since tamoxifen has a
complex metabolism, it is prone to drug-drug interactions with herbs and
supplements as was shown previously with curcumin. Furthermore, a study in rats
demonstrated a significant 43% increase in AUC of tamoxifen when treated with
green tea supplements suggesting P-glycoprotein (P-gP) and CYP3A4 inhibition or
improved tamoxifen absorption.

Since many patients use green tea supplements in addition to their anticancer
therapy a drug-drug interaction, resulting in increased (better absorption and
inhibition efflux pump) or decreased (OATP1B1 inhibition) tamoxifen and
endoxifen concentrations, and therefore may have serious clinical impact in
these cancer patients.
Furthermore a clinical study in human demonstrated significant inhibition of
the organic anion transporting polypeptide 1A2 (OATP1A2), which acts as an
influx transporter in the gut, with 700 mL green tea with a high amount of
catechins (1.54 mg/mL) leading to 85% decrease in exposure to the OATP1A2
substrate nadolol. Green tea supplements appears to be a substance with a high
interaction potential in the clinical setting and therefore may deprive
patients from optimal therapy or increase therapy related side-effects.

Primary objective:

1. To compare the change from baseline of the Area under the curve (AUC) of
tamoxifen in patients with breast cancer treated with tamoxifen with and
without green tea supplements.

Secondary objectives:

1. To compare the Area under the Curve (AUC) of endoxifen in patients with
breast cancer treated with tamoxifen with and without green tea.
2. To compare other tamoxifen and endoxifen pharmacokinetic outcomes (i.e.
clearance, maximum concentration (Cmax), minimal concentration (Ctrough) and
time until maximum concentration (tmax) and elimination half-life (t*)). in
patients with breast cancer treated with tamoxifen with and without green tea.
3. To evaluate the incidence and severity of side-effects of treatment with
tamoxifen in absence and presence of green tea.

This is a 2-period, randomized, cross-over pharmacokinetic study.

Fourteen patients on steady-state tamoxifen treatment will be randomised into
two different sequences. Depending on which randomization sequence patients
will start with tamoxifen alone (sequence AB) followed by tamoxifen with green
tea supplements for 14 consecutive days or vice versa (sequence BA). Patients
will be admitted to the hospital for 24-hour blood sampling on days 14 and 28
of the study for pharmacokinetic analysis.

Patients with breast cancer will be treated with tamoxifen as standard of care.
Patients consented for this study will be randomised into 2 sequence groups
consisting of 2 phases. In phase A patients will only use tamoxifen and in
phase C patients will use tamoxifen concomitantly with green tea capsules for
14 consecutive days. During the 24 hour pharmacokinetic measurement, patients
are admitted to the hospital twice for an overnight stay (2 times 24 hours),
during which 13 pharmacokinetic blood withdrawals of 6 mL will be performed.
Major risks are not expected for tamoxifen, as tamoxifen is registered as
standard of care. Since green tea is given for a short period of time (14
days), no major risks are to be expected. Nonetheless, we will carefully
observe all included patients using a patient diary and two-weekly phone or
clinical appointment, during the whole study period.