A combined medication safety assessment of rivaroxaban with Tyrosine Kinase Inhibitors for cancer patients: focusing on CYP2J2 and CYP3A4
Tingting Zhaoa,b #, Xuening Lia, b, #, Yanwei Chenc, #, Dalong Wanga, Liyan Wangc, Shan Zhaod, Changyuan Wanga, b, Qiang Menga, b, Huijun Suna, b, Kexin Liua, b, Jingjing Wua, b*
aDepartment of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
bProvincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China.
cDepartment of Pharmacy, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
dDalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
# These authors contributed equally to this work.
* Correspondence:
Dr. Jingjing Wu
ORCID: 0000-0002-5046-9996
Department of Clinical Pharmacology, College of pharmacy
Dalian Medical University
9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China
Abstract
Background and purpose: Cancer patients are always complicated with vein thromboembolism, thus the combination of anticoagulants with anti-cancer drugs has profound foundations. This study aimed to assess the safety of rivaroxaban comminating with three tyrosine kinase inhibitors (TKIs) in cancer patients.
Experimental Approach: The inhibition of three TKIs on CYP2J2- and CYP3A4-mediated rivaroxaban metabolism was first screened and then reversible and mechanism-dependent inhibitory kinetic constants were determined. Molecular docking was conducted to reveal the interactions between TKIs and CYP2J2 and CYP3A4. Finally, pharmacokinetic parameters of cancer patients were used to assess the safety.
Key Results: Imatinib and gefitinib significantly reversibly inhibited CYP2J2- and CYP3A4-mediated rivaroxaban metabolism, while sunitinib only showed reversible inhibition of CYP3A4, not CYP2J2. Three TKIs also showed time-dependent inactivation of CYP3A4. Notably, sunitinib had the strongest inactivation effect on CYP3A4 than the other TKIs with a 4.00-fold IC50 shift, however, a slight effect on CYP2J2. Docking simulations revealed the relation of inhibitory activity to ChemScore. Additionally, drug-drug interaction risks of combinations were assessed using pharmacokinetic data of cancer patients. Imatinib, which showed the strongest inhibition, was predicted to cause a 114–244% increase in rivaroxaban exposure.
Conclusion and Implications: Imatinib was predicted to have a moderate DDI risk when was combined with rivaroxaban. These results provide evidence for medication guidance when combining rivaroxaban with TKIs for cancer patients, and also give new insight for the DDI assessment involving rivaroxaban.
Keywords:combined medication, CYP2J2, CYP3A4, drug-drug interaction, medication safety
Introduction
Cancer patients are one of the target populations of anticoagulation. Cancer-related vein thromboembolism (VTE) is closely associated with increased morbidity and mortality, and thrombotic diseases have been the leading cause of non-neoplastic death in cancer patients (Song, Rosovsky, Connors & Al-Samkari, 2019; Timp, Braekkan, Versteeg & Cannegieter, 2013; Zamorano et al., 2016). According to statistics, cancer patients have an approximately 4–7-fold higher risk of VTE than normal patients, and cancer patients with VTE account for about 20% of all VTE patients (Blom, Doggen, Osanto & Rosendaal, 2005; Streiff, 2016). Compared with non-cancer patients, the recurrence rate of VTE in cancer patients is 3–4 times higher and the incidence of major bleeding is also increased by 2–3 times (Douketis, Crowther, Foster & Ginsberg, 2001; Levitan et al., 1999; Monreal et al., 2006; Prandoni et al., 2002). In cancer patients, the presence of tumours is one of the major risk factors for VTE. Also, both the hypercoagulability of cancer patients and the thrombogenicity of anti-cancer agents are reasons (Shalhoub et al., 2017; Zamorano et al., 2016). In addition to VTE, the risk of atrial fibrillation (AF) for cancer patients was also extremely high (Onaitis, D’Amico, Zhao, O’Brien & Harpole, 2010). An analysis showed that the occurrence of AF for cancer patients in the 90 days after the cancer diagnosis was much higher than for normal patients (Saliba, Rennert, Gronich, Gruber & Rennert, 2018). And notably, the prevention of stroke and systemic embolism by using anticoagulants is one of the therapeutic cornerstones of AF management (January et al., 2019). Therefore, coagulation prevention or anticoagulant treatment is unavoidable in cancer patients. Thus, cancer patients may receive anticoagulant therapy concurrently with anti-cancer therapy.
For decades, anticoagulant therapy for cancer-related VTE has been limited to vitamin K antagonists (VKAs) and heparin drugs. Recently, direct oral anticoagulants (DOACs) have also become an option (Streiff et al., 2020). Rivaroxaban is recommended for the treatment of superficial vein thrombosis and VTE prophylaxis following the discharge by the National Comprehensive Cancer Network of America in 2020 of the clinical practice guidelines for cancer-associated venous thromboembolic disease (Streiff et al., 2020). Additionally, data from large randomised clinical trials also demonstrated that DOCAs combined with validated risk assessment scores are a reasonable choice for the primary thromboprophylaxis of cancer patients instead of low molecular weight heparin (Song, Rosovsky, Connors & Al-Samkari, 2019). Furthermore, the ease of taking this medicine improves patient adherence. Thus, DOCAs, especially rivaroxaban, may become an alternative to the standard therapy for cancer patients.
The co-medication safety assessment of rivaroxaban is still lacking. Rivaroxaban is widely used for the prevention and treatment of thromboembolic disorders in clinical practice. Although in vivo pharmacokinetic data are stable, bleeding is still a risk factor that should be considered for medication safety. Our previous studies have shown CYP2J2 and CYP3A4 to be the major isoforms involved in the metabolic process of rivaroxaban, and importantly CYP2J2 showed ~39-fold higher catalytic efficiency than CYP3A4 (Zhao et al., 2021). CYP3A4 is always considered as the enzyme which resulted in drug-drug interactions (DDIs), however, CYP2J2 is always ignored due to its lower abundance in the liver. CYP2J2 is a P450 isoform that is mainly distributed in the heart and arteries, which is responsible for the metabolism of arachidonic acid. Notably, CYP2J2 was recently highlighted as an emerging tumour marker. Numerous studies have reported the high expression of CYP2J2 in various cancer cell lines, tumour tissues and even in the liver of cancer patients, which may relate to tumour expansion and metastasis (Allison et al., 2017; Karkhanis, Hong & Chan, 2017). Therefore, the status of CYP2J2 in rivaroxaban DDI research cannot be ignored. However, safety assessment data on medication combinations are lacking, so the related roles of CYP2J2 are unknown.
Tyrosine kinase inhibitors (TKIs) are the most commonly used drugs against cancers clinically. Among these, imatinib, sunitinib and gefitinib have been the mainstay treatments for various solid tumours since their launch in 2000 (Burotto, Manasanch, Wilkerson & Fojo, 2015; Cheng et al., 2013; Kuczynski, Lee, Man, Chen & Kerbel, 2015; Tirumani, Jagannathan, Krajewski, Shinagare, Jacene & Ramaiya, 2013; Wertheimer et al., 2015). Imatinib was almost the first TKI anti-tumour drug to gain approval by the US Food and Drug Administration (FDA), and imatinib has become a first-line clinical drug for gastrointestinal stromal tumours (GIST) (O’Brien et al., 2003; von Mehren & Widmer, 2011). However, due to the long treatment cycles, the safety of imatinib in combination with other drugs is particularly important (Guilhot, 2004; Nebot, Crettol, d’Esposito, Tattam, Hibbs & Murray, 2010). As a multitargeted TKI, sunitinib exerts strong angiogenesis inhibitory activity. It was approved by the FDA in 2006 as a first-line drug for metastatic renal cell carcinoma, and it was also used as a second-line drug for imatinib-resistant patients (Kalra, Rini & Jonasch, 2015). Gefitinib was the first TKI to gain approval in the US and Japan for treating advanced non-small-cell lung cancer (NSCLC), and it can significantly prolong the progression-free survival of NSCLC patients (Dhillon, 2015). It is noteworthy that CYP3A4 accounts for a considerable proportion of the CYP-mediated metabolism of these three TKIs, which is similar to rivaroxaban. Indeed, it is the overlap between the metabolic enzymes for rivaroxaban and these three TKIs that may produce DDIs.
The guidelines of combinations of DOCAs with other drugs were always cautious. American Society of Hematology recommended that DOCAs should be replaced with other anticoagulation when in coadministration with strong CYP inducers or inhibitors based on low certainty in effectiveness and safety (Witt et al., 2018). But it is unreasonable to completely deny DOCAs combinations in clinical practice. Imatinib, sunitinib and gefitinib have been widely applied for patients with solid tumours. Thus, the comitant administration of rivaroxaban with these three TKIs has a profound combination foundation in the treatment of cancer patients, and the safety of this combination deserves further attention. However, assessment data on the safety of rivaroxaban with TKIs is limited. Hence, more relevant and detailed pharmacokinetics measurements are required. The present study assessed the DDI risk of the combination of rivaroxaban with the three TKIs by in vitro enzyme assays. Importantly, the investigation was mainly performed on CYP2J2 and CYP3A4 to comprehensively explore their reversible and time-dependent inactivation behaviours. Finally, the in vivo DDI risk of the combination of rivaroxaban with the three TKIs was estimated according to detailed pharmacokinetic parameters of cancer patients, producing direct evidence to inform clinical medication safety assessment.