Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity.

BACKGROUND: Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib. OBJECTIVE: To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity. METHODS: This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study. RESULTS: Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing. CONCLUSION: In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

[Effects of Seven Tyrosine Kinase Inhibitors on the Anticoagulation Activity of Warfarin].

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.

[Effects of Tyrosine Kinase Inhibitors on Control of PT-INR in Patients Receiving Warfarin].

Few studies have evaluated the influence of anticancer drugs on the anticoagulation response to warfarin(WF). This retrospective, single-center, observationalstudy evaluated the changes in prothrombin time-internationalnormal ized ratio (PT-INR)in patients receiving a combination of WF and anticancer drugs. We compared(a)PT-INR changes between groups receiving WF and concomitantly started on either tyrosine kinase inhibitors(TKI)(WF+TKI group: n=14)or anticancer drugs other than TKI(WF+non-TKI group: n=20)and(b)PT-INR changes between groups that were started on WF concomitantly while receiving either TKI(TKI+WF group: n=16)or anticancer drugs other than TKI(non-TKI+WF group: n=13). (a)PT-INR changes were significantly larger in the WF+TKI group than in the WF+non-TKI group(2.23 vs 0.42, p<0.001). In the WF+TKI group, the WF dose was reduced after all 14 patients(100.0%)showed increased PT-INR.(b)PT-INR changes during the WF induction period were significantly larger in the TKI+WF group than in the non-TKI+WF group(2.18 vs 0.68, p<0.001). In the TKI+WF group, the WF dose was reduced after 12 patients(75.0%)showed increased PT-INR. It might be necessary to consider a reduction in WF dose when WF is administered in combination with TKIs.

Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers.

PURPOSE: The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. METHODS: The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. RESULTS: We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035). CONCLUSION: This study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.

Identification of risk factors for venous thromboembolism and evaluation of Khorana venous thromboembolism risk assessment in Japanese lung cancer patients.

BACKGROUND: The reported incidence of venous thromboembolism (VTE) in cancer patients is 4-20%. The Khorana VTE risk score (KRS) and the Vienna VTE risk score (VRS) have been proposed as scoring models for evaluation of cancer-associated VTE. However, the risk factors of VTE in Japanese lung cancer patients have not been clarified. METHODS: This retrospective study included 682 hospitalized Japanese patients with newly diagnosed lung cancer who were examined for VTE on admission between January 2014 and December 2016. RESULTS: Seventy-one (10.4%) of the 682 patients were diagnosed with VTE. Multivariate logistic regression analysis showed that body mass index (BMI) ≥25 kg/m2 (OR, 2.02; 95% CI, 1.06-3.72), white blood cell (WBC) count >11 × 109/L (OR, 2.31; 95% CI, 1.11-4.61), pre-chemotherapy serum D-dimer concentration ≥1.44 µg/mL (OR, 2.73; 95% CI, 1.49-4.99), and non-small cell lung cancer (OR, 3.13; 95% CI, 1.32-9.23) were significantly associated with VTE in these patients. The cut-off values for BMI, WBC count, and D-dimer concentration determined using receiver operating characteristic curves were 25.4 kg/m2, 11.2 × 109/L, and 1.95 µg/mL, respectively. CONCLUSIONS: In this study, we were able to identify four independent risk factors for cancer-associated VTE in Japanese lung cancer patients for the first time. Moreover, we showed that a cut-off level of ≥25 kg/m2 for BMI was a risk factor for VTE in this cohort.