1 Introduction
Multi-kinase inhibitors (MKIs), particularly tyrosine kinase inhibitors
(TKIs) have rapidly become an established factor in oncology, and have
been shown to be effective in a wide variety of solid and hematologic
malignancies1-3. The
oral administration route of TKIs offers logistic flexibility and is
convenient for the patients, however, despite these advantages, it also
causes a highly relevant new problem. Of recently approved orally
administered cancer therapeutics, >50% are characterized
as having pH-dependent
solubility4-6. The poor
and variable pH-dependent solubility, together with other variable
pharmacokinetic factors, contribute to a significant patient variability
in plasma levels and exposure. Next to other factors, TKI therapy is
associated with a higher risk for gastrointestinal disorders. A majority
of cancer patients frequently take acid–reducing agent (ARA) to
alleviate gastroesophageal symptoms, thereby raising the potential for a
gastric pH-dependent drug
interaction4. This type
of DDI may have detrimental effects on the efficacy of TKIs, with major
clinical impacts described for some orally administrated targeted
therapies (erlotinib, gefitinib, pazopanib, palbociclib), and
conflicting results with many others, including nilotinib or
dasatinib4,7,8.
Long-term suppression of gastric acidity could decrease the absorption
of certain major oral anticancer drugs with pH-dependent solubility and
result in subsequent failure of therapy. To address this, guidelines are
provided by the FDA and the European Medicines Agency (EMA) that
recommend studying the DDI between pH-dependent drugs and ARAs.
Famitinib (famitinib-malate, SHR1020) is a novel and potent
multi-targeted receptor TKI that targets at c-kit, vascular endothelial
growth factor receptor 2 and 3 (VEGFR-2 and 3), platelet-derived growth
factor receptor (PD-GFR), FMS-like tyrosine kinase-3 receptor (FLT3) and
protooncogene tyrosine kinase receptor (RET)9,10.
Famitinib is a structural analog of sunitinib with improved cell
inhibitory activity. Due to its anti-angiogenic effect, it was effective
against metastatic renal cell carcinoma, non-small cell lung cancer and
metastatic breast cancer11-13. Clinical trials
of famitinib in combination with the concurrent medication or
chemoradiotherapy also showed its good antitumor abilities against other
solid tumors such as metastatic urothelial carcinoma, advanced
immunomodulatory triple-negative breast cancer, advanced nasopharyngeal
carcinoma, platinum-resistant recurrent ovarian cancer, advanced
colorectal cancer and gastric
cancer9,14-20.
A phase I study showed that famitinib had favorable PK characteristics
and was generally well-tolerated. After a single oral administration of
famitinib, it was well absorbed and extensively metabolized. The major
circulating metabolite SHR116637 was the formation of N-desethyl
famitinib, which is pharmacodynamically active but exhibits a lower
potency than the parent
drug21. Within the
dosing range of 4–27 mg, the increase in C maxand AUC 0–24h for famitinib and SHR116637 were
proportional to the increase in dose level, T maxof the parent drug and the major metabolite SHR116637 in cancer patients
occurred within 3.3–5.3 and 4.0–6.2 h, respectively. The plasma level
of SHR116637 is approximately equivalent to 3.6 % of that of the parent
drug, and both famitinib and SHR116637 were slowly removed from
circulation9. After
administration for 28 days, the degrees of famitinib accumulation in
vivo were significantly lower than sunitinib and the major side effects
were noted in terms of neutrocytopenia, thrombocytopenia, diarrhea,
fatigue and peripheral edema, with particularly less severe fatigue and
thrombocytopenia9. These
toxicities had no significant accumulation while treatment proceeded,
however, the common adverse events (AEs) of gastrointestinal reactions,
such as nausea and diarrhea, needed ARAs and gastric mucosal protective
to alleviate these adverse events.
Although ARAs are extensively used during anticancer treatment, there is
still much controversy on how to manage drug–drug interactions (DDIs)
between TKIs and
ARAs22. Early
assessment of pH-dependent DDIs for TKI of poorly soluble and weakly
acidic compounds offers various advantages for patient safety. Famitinib
has been classified as a BCS class IV drug (low solubility, low
permeability) by the FDA. The results of in vitro solubility test showed
that the solubility of famitinib was 85, 140 and 8 μg/mL in the medium
system of pH 1.0, 4.5, 6.8 respectively. The magnitude of solubility
change with increasing pH occurs at a pH of 6.0-6.8. According to the
FDA guidance’s decision tree on the evaluation of gastric pH-dependent
drug interactions, DDI studies with ARAs are required if the drug
dissolution is too low to determine the effect of pH on drug solubility
or the solubility of the drug at pH 6.0–6.8 is less than dose divided
by 250 mL5. Famitinib
fits both of these criteria, so it is necessary to explore the effects
of pH on the PK of famitinib, including maximum plasma concentration
(C max), area under the curve (AUC), and other PK
parameters. Among all therapeutic agents, PPIs are the most prevalent
and most potent ARAs and with daily use produce a marked and sustained
duration of acid
suppression4,5.
A prospective study in four French Comprehensive Cancer Centers, more
than a quarter of cancer patients used PPIs, mostly on a daily basis and
in the long term23. As
PPIs generally have a longer duration of suppression effect on gastric
acid secretion than H2 blockers and antacids do, they
are expected to interfere with the intestinal absorption of TKIs to a
greater extent. In this paper, omeprazole, was therefore chosen for the
study of famitinib with an ARA. We aim to update the potential gastric
pH-dependent drug interactions between omeprazole and famitinib in
healthy subjects, as well as to ascertain the safety of
co-administration of famitinib and omeprazole.