4.Disscusion
Since the usage of PPI is associated with decreased TKI efficacy,
prescribers are posed with a great dilemma whether or not to continue
the combined treatment. To our knowledge, this is the first study to
assess the PK and safety effects of omeprazole on the potent MKI
famitinib as well as its major
metabolite SHR116637 in healthy subjects. Our findings suggested that
omeprazole did not significantly impact the PK properties of both
famitinib and SHR116637, demonstrating good safety on co-administration.
Key factors in the design of a pH-dependent DDI study include study
population, selection of ARAs, type of crossover design (randomized or
single-sequence), and the dose/dosing regimen
etc5. Previous clinical
trials have demonstrated that famitinib showed linear dose-related
pharmacokinetic characteristics in the dosing range of 4-27 mg. The
recommended dose for phase II clinical trials is 25 mg. Hence, for the
safety evaluation, the dose of famitinib was selected to be 25 mg. The
main PK parameters were similar in terms of C max,AUC and t 1/2 between the patients with
advanced solid cancer and healthy subjects. Food intake was unlikely to
impact on the PK of famitinib9. Ideally, the DDI
results obtained in this study under fasting condition can help guide
cancer patients’ treatment. Furthermore, Multiple enzymes, mainly
CYP3A4/5 and CYP1A1/2, are involved in famitinib metabolic clearance.
And it is also a weak inhibitor of CYP3A4, in vitro study,
however, it’s unlikely to affect CYP3A4 due to a single dose of
famitinib at 25 mg. As a result, omeprazole was chosen for the DDI
study, it gives its high affinity for CYP2C19 and moderate affinity for
CYP3A, which could show little influence to the systemic exposure of
famitinib and SHR116637. And a self-control study was also used to
overcome the influence of enzyme differences between individuals.
Compared with famitinib single-dose administration, the geometric mean
of AUC 0-∞ was slightly reduced when famitinib was
co-administered with omeprazole (1417.927 vs. 1351.939 h·ng/mL,
decreased by approximately 4.7%), along with theC max, T max,t 1/2, CL/F and Vz/F did not significantly differ
between the two phases. The least squares GMRs ofC max, AUC 0-t andAUC 0-∞ (90% CIs) of famitinib combined with
omeprazole to famitinib alone were 0.989 (0.953, 1.027), 0.956 (0.907,
1.007) and 0.953 (0.905, 1.005)
respectively, indicating the absence of significant differences inAUC 0-t, AUC 0-∞ andC max of famitinib when compared with famitinib
alone. The metabolite SHR116637 data was consistent with the reduced
absorption famitinib, and the metabolic ratio remained similarly small
for both treatment arms with 0.075 versus 0.081 for famitinib and
famitinib plus omeprazole, respectively. The medianT max of famitinib metabolite SHR116637 was 5.00 h
and 6.50 h, indicating that the peak time of famitinib metabolite
SHR116637 was slightly prolonged after omeprazole combined with
famitinib. The C max,AUC 0-t and AUC 0-∞decreased by 14.9%, 11.0% and 11.3% for famitinib and famitinib plus
omeprazole, respectively. The least squares GMRs ofC max, AUC 0-t andAUC 0-∞ (90% CIs) of SHR116637 between
coadministration group and alone group were 0.851 (0.786, 0.920), 0.890
(0.838, 0.946)and 0.887 (0.835, 0.943) respectively. Except the lower
limit for the SHR116637 GMR of C max (90% CIs) is
78.6%, the least squares GMRs of AUC 0-t,AUC 0-∞ and C max (90% CIs)
of both famitinib and SHR116637 are all in the range of 80%-125%.
Compared the “no concomitant PPIs” versus “concomitant PPIs” based
on their clinical characteristics, the exposure of metabolite SHR116637
is approximately equivalent to 9.47% and 8.72% of that of the parent
drug, so it has little effect on the PK of famitinib. In general, there
was no significant difference in the exposure, absorption, distribution
or elimination of famitinib, indicating that omeprazole did not have a
significant influence upon the PK parameters of famitinib.
According to one completed phase-I clinical trial, the most common AEs
of famitinib included neutrocytopenia, thrombocytopenia, diarrhea,
fatigue and peripheral edema. In some cases, it can also result in
elevation of blood lipids and
glucose9,21.
In our study, we also assessed the safety profile of combination therapy
in the present study, compared with the above AEs, most AEs observed in
the present study was mild or moderate, such as increased gamma-glutamyl
transferase, increased basophil count, increased heart rate, alanine
aminotransferase, blood glucose increased, blood triglycerides elevated,
the positive urine test for leukocyte-esterase and sugar. During the
treatment period, a total of 6 (30.0%) subjects had 9 AEs during
famitinib alone, and 1 (5.0%) subject had 1 AE during the mutiple dose
of omeprazole, while 5 (25.0%) subjects had 6 AEs during famitinib
combined with omeprazole. Less severe and less frequent side effects
were noted after the co-administration of omeprazole and
famitinib compared with the
single phase of famitinib, revealing the safety and tolerability of
famitinib and omeprazole coadministration in clinical settings.
Co-administration of famitinib and omeprazole was associated with good
safety.
In this single-center, open, single-dose and self-control study, use of
a PPI may be considered a worst-case scenario in the in vivoevaluation of the pH effect. If a PPI does not result in any clinically
relevant effect on the absorption of a weak base drug, further dedicated
DDI studies with other classes of ARAs may not be necessary. The common
dose of omeprazole is 20 mg qd, which can achieve maximum suppression of
gastric acid within ~ 4 days, and the expected effect of
a 40-mg dose follows a similar
time-course24.
Therefore, 40 mg of omeprazole was administered for 5 consecutive days
in our study, and a second dose of famitinib was administered 5 days
after omeprazole administration to ensure that subjects achieved maximum
inhibition of gastric-acid secretion.