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.