3.4 Safety
3.4.1 TEAEs
There were 15 subjects suffering 28 adverse events during the research.
Of the 15 subjects. No subjects reported any TEAEs in the phase of a
single dose of SHR2554, 7 subjects reported 8 TEAEs in the phase of
multiple doses of rifampin, and 13 subjects reported 20 TEAEs during the
phase of coadministration.
The TEAEs recorded in this study were grade 1, grade 2, or grade 3
severity (per the National Cancer Institute Common Criteria for Adverse
Events version 5.0). there were 14(77.8%) subjects suffering from 26
grade 1 TEAEs, 1(5.6%) subject suffering from 1 grade 2 TEAEs
(Dearticulation reported in the phase of coadministration with
rifampin), and 1 subject suffering from 1 grade 3 TEAEs (Epilepsy
reported in the phase of coadministration with rifampin). The main grade
1 TEAEs included: nausea, diarrhea (55.6%, reported in the phase of
coadministration with rifampin), various examinations (27.8%, reported
in the phase of multiple doses of rifampin; 11.1%, reported in the
coadministration with rifampin), dizziness and headache (33.3%,
reported in the coadministration with rifampin), metabolic and
nutritional diseases (11.1%, reported in the phase of multiple doses of
rifampin).
There were 15(83.3%) subjects suffering from 26 SHR2554-related TEAEs,
including 7 TEAEs reported in the phase of multiple doses of rifampin,
and 19 TEAEs reported in the phase of coadministration with rifampin.
There were no TEAEs leading to death in our study, and one subject
withdraw from the study due to serious TEAEs. The information could be
found in Tables 4 and 5.
3.4.2 Other safety endpoints
Table S1 listed all clinically significant changes in laboratory
findings, vital signs, and physical examinations. There were no abnormal
or clinically significant ECG changes observed during the treatment
period.
4 Discussion
Based on The Food and Drug Administration (FDA) and European Medicines
Agency’s guidelines, strong index metabolic enzyme inhibitors and/or
inducers should be preferentially incorporated in drug-drug interactions
clinical studies if the investigational drugs have been demonstrated
metabolism by such enzymes. In addition, previous pre-clinical studies
have demonstrated that CYP3A4 participated in the main oxidative
metabolism of SHR2554, and the phase I clinical trial indicated that
potent CYP3A4 inhibitor itraconazole could significantly increase the
exposure of SHR2554[16]. Therefore, this study was
designed to appraise the potential effect of rifampin on the PK
properties of SHR255 in healthy Chinese subjects and assess the safety
of drug-drug interactions.
The finding of this DDI study proved that powerful CYP3A4 inducer
rifampin significantly impacted the PK characteristics of SHR2554 in
Chinese healthy volunteers. Besides, SHR2554 coadministration with
rifampin showed good safety and acceptable tolerance with only reported
mild to moderate severity TEAEs. Considering the alto-frequency of drug
combination in tumor patients, it is notable to take it into account for
doctors when concomitant using SHR2554 and potential inducers of CYP3A4.
In general, the recommended introduced dose for rifampin is 600mg
daily(about 8-12 mg/kg), with full induction of drug-metabolizing
enzymes reached in about 1 week after starting rifampicin
treatment[17]. Enzymes and transporters returning
to pre-treatment levels may need at least 24 days after the end of
treatment[18]. But some patients with several
tuberculosis would adjust the dosage to 35mg/kg for high cure rates due
to its dose-dependent bactericidal activity, which significantly
exceeded the recommended dose[19]. In order to
minimize unnecessary drug exposure for subjects and ensure obvious
induction to CYP3A4 enzyme at the same time, a dose of 600mg daily for a
week was considered in our study. Due to the dose-dependent and
concentration-dependent induction for CYP3A4[20],
the induction in absorption to co-administered medicines in actual
clinical settings by rifampin would be extremely higher than the results
expressed in this trial. Therefore, therapeutic strategies should be
considered to avoid the combination of these two agents whenever
possible.
Compared to reported drug-drug interaction results between rifampin and
other drugs, our study founding suggested that concomitant
administration of rifampin significantly decreases the exposure process
of SHR2554 in vivo, resulting in extremely remarkable decreases in
Cmax, AUC0-t, and AUC0-∞by 89%, 93%, and 93%, respectively. This revealed that CYP3A4 plays
an important role in the metabolic process of SHR2554 and any DDI with
potent CYP3A4 enzyme inducers should be carefully monitored in SHR2554
therapy.
What’s more, a nearly 89% decrease in Cmax indicated
that the absorption of SHR2554 may also be affected after
coadministration with rifampin, which is similar to the increase of
VZ/F. Preclinical results have demonstrated
permeability-glycoprotein (P-gp)
may participate in SHR2554 PK process[21]. P-gp is
widely distributed on apical membranes of various cells, which limits
drug absorption, penetration, and elimination leading to a decrease of
drugs in cells[22-24]. Rifampin, as the reported
maximal induction of P-gp[25], could reduce the
Cmax of orally administered P-gp substrates by
19-69.5%, thereby reducing the concentration of SHR2554. Despite
rifampin-induced P-gp and CYP3A4 expression to a similar extent as well
as both being involved in metabolism of
SHR2554[26], the magnitude of the decrease of
SHR2554 exposure by P-gp is generally lower than CYP3A4
enzyme[27]. Most of the alterations of PK
parameters should be attributed to the induction to the CYP3A4 enzyme by
rifampin.
Our results suggested a single dose of 300mg SHR2554 performed good
safety and well-tolerance in healthy subjects, with no TEAEs happening
during the single administration; whereas all TEAEs happened during the
phases of multiple doses of rifampin and coadministration with rifampin.
However, it is difficult to discriminate TEAEs ascribed to SHR2554 or
rifampin because of the commonality of TEAEs for both SHR2554 and
rifampin. Generally, in the completed or ongoing clinical trials, the
most common non-hematological drug-related TEAEs were nausea, dizziness,
diarrhea, and etc.; besides, the drug-related TEAEs in hematology were
hypercholesterolemia, anemia, increased alanine aminotransferase,
decreased neutrophil, and etc. In contrast to previously published
literature in patients with relapsed or refractory mature lymphoid
neoplasms and healthy volunteers, there are several differences in the
category and incidence of adverse events[15],
which may attribute to the effect of rifampin on SHR2554 led to
different category and incidence of adverse events, but the most
impossible reason might be disease condition and individual factors.
Furthermore, this study chose single dose of 300mg, higher than the dose
of 50mg in completed tiral in healthy volunteers. Beside, the
experimental design and days of administration also should be
incorporate into potential factor which cause different adverse events.
Overall, it is necessary to monitor the adverse events, especially for
hematological toxicity during the treatment coadministration with
rifampin or other CY3A4 induces.
Ingestion with food would decrease the absorption of rifampin and
prolong the time to Cmax, resulting in decrease
Cmax and AUC by 36-40%, and 6-26%,
respectively[28-31]. In addition, the instruction
of rifampin recommends rifampin be taken before meal to ensure maximal
absorption considering to the concentration-lowering influence of food
reducing about 30% of absorption of rifampin. And previous clinical
trial has demonstrated food effects involved in the absorption of
SHR2554(NCT04335266). Therefore, SHR2554 and rifampin were both
administrated in fasting condition to keep the administration method
consistent, as well as to reduce the variability in absorption.
In order to exclude residual confounding effects to PK process as far as
possible, such as comorbidities and concomitant medications, this study
was perform in healthy subjects to evaluate the DDI between SHR2554 and
rifampin. It indicated that rifampin, a CYP3A4 enzyme inducer, has
strong interaction with SHR2554, which could significantly decrease the
exposure and promote the elimination of SHR2554. Suggested that patients
should avoid drug combination of SHR2554 and rifampin in general or try
to reduce the dose of rifampin to guarantee efficacy of SHR2554.
Regrettably, lower doses of rifampin or other moderate inducers for
CYP3A4 enzyme was not been considered in this study, which should be
conducted relevant studies in the future to help researchers understand
deeply for DDI potential of the investigational drug. Meanwhile, the
induction for SHR2554 could be assessed through modeling and simulation
methods or in clinical interaction studies. Given the innovations and
prospect, SHR2554 would be frequently used for various tumors, the
results could provide some valuable references for researcher to design
and conduct subsequent clinical II/III trials and better development of
SHR2554.
Conclusion
The results showed that rifampin could significantly impact the
properties of SHR2554 in Chinese healthy volunteers. It is recommended
to avoid concomitant use of SHR2554 and strong inducers of CYP3A4.
AcknowledgementsThe authors wish to acknowledge and thank the study participants and the
investigating team at Xiangya Hospital and Hunan Provincial Natural
Science Foundation of China (No. 2020JJ9022). This trial was sponsored
by Jiangsu Hengrui Pharmaceuticals Co., Ltd.