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.