Influence of Flavonoids on the Absorption of Nintedanib: a Randomized, Cross-Over Pharmacokinetic Study (the INFLATE study)

Nintedanib is a multi-targeted oral tyrosine kinase inhibitor, registered as
first-line monotherapy (150 mg BD) in the treatment of IPF. IPF is an orphan
disease, with a prevalence and incidence of 28 and 17 patients per 100.000
people, respectively. In The Netherlands, there are over 2.000 IPF patients, of
which 100-150 are treated with nintedanib in the Erasmus MC. Patients with IPF
have a median survival of 3 years and a 5-year survival of only 34%. Nintedanib
inhibits multiple pathways which cause progression of lung fibrosis, resulting
in overall survival benefit of two years.
Recent studies showed that nintedanib has activity in interstitial lung
diseases (ILD), and registration for these diseases, as hypersensitivity
pneumonitis (c.q. chronic extrinstic allergic alveolitis) and non-specific
interstitial pneumonia, is expected. Herewith broadening its indication by
becoming the sole registered treatment for this indication, 700-800 more
patients are expected to be treated with nintedanib. In the Erasmus MC,
patients with IPF are treated with nintedanib, both as regular care, within
clinical trials and in an early access program.
The common toxicities are: diarrhoea (> 60%), nausea (> 22%), vomiting (> 12%)
and elevated liver enzymes. More than 30% of patients experienced serious
adverse events during treatment, leading to death, life-threatening situations,
clinically significant disability or incapacity or hospitalization. Nintedanib
is advised to be administered concomitantly with food, since then its
bioavailability increases with 20% and less side effects are experienced.
Nintedanib*s bioavailability is 4.7% and it is metabolized by CYP3A4 for just
5%. Drug-drug interactions with CYP-enzyme inhibitors or inducers are therefore
not likely. However, nintedanib is a substrate of the efflux pump
P-glycoprotein (P-gP). P-gP is present in the gastro-intestinal tract and
blood-brain barrier. It plays a key role in active cellular drug excretion c.q.
reducing absorption, which causes lower drug exposure. Furthermore, P-gP
upregulation in (cancer) cells is one of the described resistance mechanisms to
for example anti-cancer treatments. P-gP can be inhibited by flavonoids,
especially by epigallocatechin gallate (EGCG). ECGC is highly concentrated
found in the popular beverage green tea. Based on European Food and Safety
Authority scientific opinion, 300 mg of EGCG is considered the general daily
intake from consumption of green tea, which increases to 866 mg EGCG/day for
high-level consumers. 300 mg EGCG is comparable to 700 ml (5 to 6 cups) of
green tea. In most labels of green tea extract capsules it is advised to take
at least twice this dosage, up to 1,000 mg EGCG/day. In the presence of 10 µl
ECGC, drug efflux (c.q. resistance) in P-gP overexpressing cell lines decreased
with 7- to 8.5-fold. Hence, the flavonoid-drug interaction could potentially
lead to higher nintedanib absorption by the gastro-intestinal tract. This would
cause higher systemic bioavailability and lower local gastro-intestinal drug
concentrations (which is thought to be causing most of nintedanib*s toxicity).
Furthermore, inter-patient variability could decrease, as also seen with other
SMKI*s.

Our objective with this proposal is to study the interaction between nintedanib
and green tea capsules with > 60% ECGC in fibrotic ILD patients. Depending on
the presence and magnitude of the interaction, we will be able to give
practical recommendations for daily practice to physicians and patients.
Outcomes of this study could change current recommendations, when green tea
ECGC is found to be a potent interacting compound with nintedanib.

A randomized, two-phase cross-over pharmacokinetic study in which nintedanib
will be taken seven days with water and a meal respectively with or without 500
mg green tea capsules with > 60% ECGC extract.
The two phases consist of a control phase (A) and an intervention phase (B), in
which nintedanib will be taken seven days with water and a standardized meal
respectively with or without one capsule of 500 mg green tea extract.
- Phase A exists of 7 days in which nintedanib is taken twice daily with water
and a meal.
- Phase B exists of 7 days in which nintedanib is taken twice daily with water
and a meal and concomitant with 500 mg green tea extract.
The last day of each phase patients will be admitted for 12 hour
pharmacokinetic sampling at t=0h, t=0.5h, t=1h, t=1.5h, t=2h, t=2.5h, t=3h,
t=3.5h, t=4h, t=5h, t=6h, t=8h and t=12h. In arm 2, to prevent interference by
ECGC of phase B in phase A, a wash-out period of 14 days is designed.

Nintedanib will be used as standard care of treatment and is given in a dosage
of 100-150 mg twice daily. Dose modifications are not allowed during the whole
study period. Nintedanib will be administered for at least two weeks at the
same dose to guarantee steady-state. Nintedanib will be administered daily
around the same time, i.e. 9.00 AM and twelve hours later at 21.00 PM with
water and a meal. Green tea capsules will be given in a dosage of 500 mg twice
daily concomitantly with nintedanib.

The green tea capsules in this dosage are safe to use. Any interaction would be
of such a short period that differences in nintedanib concentration are also
significant, but not directly clinically relevant in the form of
ineffectiveness or side effects. The admission with blood draws does not pose
any additional risks than with a diagnostic blood draw, which gives a very
small risk of e.g. thrombophlebitis and a hematoma post-point.