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Studies on Venous Thromboembolism and Anticoagulation Therapy in Cancer

Patients

Ōŵ 27 ōőÉij

� � � � � � � � � � � � � � ŌÒ ʆ˥Hiraide, Makoto˦

ƃŁƏĆ

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ȓǁ

ɂɹ ………………………………………………………………………...………. 1

Ȭ 1 ȩ� ƙƩ¤Ɏ�NŬɊ7�!I˓ɖɬƴğƴȈȌȈ�d[ďı7˃(

IșȨ ……………………………………………………………………...………. 5

1.1� ȓȏ …………………………………………………………………...……... 5

1.2� ƖǑ …………………………………………………………………...……... 5

1.3� ȾƱ …………………………………………………………………...……... 7

1.4� ɉĽ ……………………………………………………………………….... 13

łƁ …………………………………………………………………………......... 17

Ȭ 2 ȩ� ��|O��4l�b�Ys�g˅Ĺɩ8ȕ¡´ǽ7˃(IșȨ

Ȭ 1 Ȱ� ��|O��4l�b�Ys�g˅Ĺɩµǽɇ /˔µǽɇ8NJʝ

…...……………………………………………………………............................. 18

1.1� ȓȏ …………………………………………………………………………. 20

1.2� ƖǑ …………………………………………………………………………. 20

1.3� ȾƱ …………………………………………………………………………. 22

1.4� ɉĽ …………………………………………………………………………. 27

Ȭ 2 Ȱ� ��|O��4l�b�Ys�g˅ĹɩµǽÙŞ8NJʝ

…...……………………………………………………………............................. 29

2.1� ȓȏ …………………………………………………………………………. 30

2.2� ƖǑ …………………………………………………………………………. 30

2.3� ȾƱ …………………………………………………………………………. 33

2.4� ɉĽ …………………………………………………………………………. 46

łƁ …………………………………………………………………………......... 54

ƩșȨ8ɁƁ …………………………….…...……………………………….… 55

ʍʡ …………………………………………………………………………......... 56

ñɉƓdz ……………………………………………………………………….… 57

Appendix ………………………………………………….………………….…… 64

Figure �ɶ

Fig. 1� ƙƩ¤Ɏ�NŬɊ7�!I VTE ȌȈ�d[ďı8ʉƲ_��qʲ

ſ ………………………………………………………………………….............. 8

Fig. 2� Body mass index�ȎɬǷƑ�D-dimer 8 VTE ȌȈ�d[ʁº7�!

I Receiver Operating Characteristics Curve ɸƯ ……..……………............ 12

Fig. 3� ËȒʐĐǑ¤�NșȨ¬Ƥƛȇˈ7�!IɎ�NŬɊ8žÐĒɩ

¶ǽDZǐ ………………….......................................................................... 19

Fig. 4� ��|O��ÇɭŽ�ɇ7�!I PT-INR8ĶɈ4žÐĒäƱ8ʁ

º …………………………………………………………………………............. 21

Fig. 5� ž�NɩÇɭŽ�ɇ7�!I PT-INR 8ĶɈ4žÐĒäƱ8ʁº

…..…………………………………………………………………………............. 22

Fig. 6� ��|O��ÇɭŽ�ɇ7�!I PT-INR Ģæʽ ………............ 24

Fig. 7� ž�NɩÇɭŽ�ɇ7�!I PT-INR Ģæʽ …...………............. 26

Fig. 8� ��|O��4l�b�Ys�g˅ĹɩµǽÙŞ7�!I PT-INR

8ĶɈ4žÐĒäƱ8ʁº ………………………………......………............ 32

Fig. 9� ��|O��4^|Qlt}�F;T��lt}8ȕ¡´ǽʉƲ

7�!I_��qʲſ …...………............................................................ 33

Fig. 10� ��|O��4 18 Ȧ8l�b�Ys�g˅Ĺɩȕ¡´ǽʉƲ7

�!I_��qʲſ …...………............................................................... 36

Fig. 11� ��|O��4^|Qlt}˥ A; n=6 �˦F;T��lt}˥ B; n=7˦

µǽÙŞ7�!I PT-INR Ģæ …...……….............................................. 40

Fig. 12� ��|O��4^|Qlt}˥ A; n=6 �˦F;T��lt}˥ B; n=7˦

µǽˁĮƜ�G PT-INRmax @38 PT-INR Ƈȣ …................................. 41

Fig. 13� ��|O��4 7 Ȧ8l�b�Ys�g˅ĹɩµǽÙŞ7�!I

PT-INR Ģæ …...………............................................................................ 44

Fig. 14� ��|O��4 7 Ȧ8l�b�Ys�g˅ĹɩµǽˁĮƜ�G

PT-INRmax @38 PT-INR Ƈȣ …...……….............................................. 45

Fig. 15� 9 Ȧ8l�b�Ys�g˅Ĺɩ˥10 µM˦7FI S-��|O��©

ʍ˅ĹǴ8NJʝ …...………....................................................................... 52

Table �ɶ

Table 1� �NŬɊ7�!I VTE ȌȈ�d[ʁºd_P …...………......... 3

Table 2� ��d�R�7�!IŬɊɐƝ …...………................................ 9

Table 3� VTE ȌȈɇ4˔ȌȈɇ7�!IɠŏȏɐƝ8NJʝ …..……….. 11

Table 4� ƙƩ¤Ɏ�NŬɊ7�!I VTE ȌȈ�d[7˃(IĤĢʽɸƯ

ȾƱ …...………......................................................................................... 12

Table 5� ��|O��ÇɭŽ�ɇ4ž�NɩÇɭŽ�ɇ8ŬɊɐƝ .... 23

Table 6� ��|O��ÇɭŽ�ɇ7�!I PT-INR Ģæʽ���|O��

Ž�ʽ�ÒɬȌǶǴ …...………................................................................ 25

Table 7� ž�NɩÇɭŽ�ɇ7�!I PT-INR Ģæʽ���|O��Ž�

ʽ�ÒɬȌǶǴ …...………....................................................................... 26

Table 8� ��|O��4l�b�Ys�g˅Ĺɩ8ɩǯ˂ȕ¡´ǽ7˃

(IƓdzƺɳ …...……….......................................................................... 29

Table 9� ��|O��4^|Qlt}�F;T��lt}µǽŬɊ7�

!IɠŏȏɐƝ …...………....................................................................... 35

Table 10� ��|O��4 7 Ȧ8l�b�Ys�g˅ĹɩµǽŬɊ7�!

IɠŏȏɐƝ …...……….......................................................................... 38

Table 11� ��|O��4^|Qlt}�F;T��lt}µǽŬɊ7�

!I PT-INR �ƚ8˜ő�ȥő�ȌǶƜƦ …...………............................ 40

Table 12 � � �|O��4^|Qlt}µǽÙŞ7�!I Time in

therapeutic range …...………....................................................................... 42

Table 13 � � �|O��4T��lt}µǽÙŞ7�!I Time in

therapeutic range …...………....................................................................... 42

Table 14� ��|O��4 7 Ȧ8l�b�Ys�g˅ĹɩµǽÙŞ7�!

I PT-INR���|O��Ž�ʽ�Time in therapeutic range …...………... 43�

Table 15� ^|Qlt}�F;T��lt}7�!I S-��|O��©ʍ

˅ĹǴ …...………..................................................................................... 51

Table 16� 7 Ȧ8l�b�Ys�g˅Ĺɩ7�!I S-��|O��©ʍ˅

ĹǴ …...………......................................................................................... 52

1

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3

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�

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thrombosis: DVT˦�I�9ɎɬƴğƴȈ˥pulmonary embolism: PE˦7Ŀ(

IžÐĒȋǑ4&2�WF E DOAC FHD LMWHs �Ȭ�ʲſɩ4&2Ƈ

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ɛʸźɮƗɭŬɊ7�!I VTE 8ȌȈżØ7ˇĶ%J2�H�@-�NŬ

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WF 8 Ž � ʽ 9 ~ � q � � { � Ɯ ˂ ē ˍ ƽ ǣ NJ ˥ prothrombin

Khorana VTE risk assessment score�KRS� Points

�Site of Cancer Very high risk Stomach, Pancreas 2

High risk Lung, lymphoma, gynecologic, bladder, testicular 1

Platelet count �350,000 /µL 1

Hemoglobin and/or erythropoiesis-stimulating agents �10 g/dl 1

Leukocyte count �11,000 /µL 1

Body mass index (BMI) �35 kg/m2 1

Vienna VTE risk assessment score�VRS�, addition of ��

D-dimer �1.44 µg/mL 1

soluble P-selectin �53.1 mg/mL 1

4

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14

Hospitalized patients with newly diagnosed lung cancer (2014/1�2016/12) �n=811)�

Patients hospitalized for treatment (n=729)

Patients with VTE (n=71)

Patients without VTE (n=611)

Excluded (n=47) ÄData insufficient (n=9) ÄPatients administering anticoagulants (n=38)

Data analysis (n=682)

VTEb\[Ê10.4Æ�

9

Table 2� ��d�R�7�!IŬɊɐƝ˥n=682˦

an (%), bMedian (range), cMean±SD ALK, anaplastic lymphoma kinase; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; KRS, Khorana risk score; NSCLC, non-small cell lung cancer; WBC, white blood cell

Characteristics

Age (years)b 67.0 (29-87)

Sex (male)a 449 (65.8)

Weight (kg)c 59.0 ± 11.9

BMI (kg/m2)c 22.3 ± 3.3

Comorbiditiesa

� Cardiovascular disease 51 (7.5)

� Diabetes mellitus 129 (18.9)

� Hypertension 235 (34.5)

� Dyslipidemia 97 (14.2)

� Chronic pulmonary disease 105 (15.4)

Smokinga 484 (71.0)

Surgerya 132 (19.4)

ECOG performance statusa

� 0-1 579 (84.9)

� 2-4 103 (15.1)

Cancer typea

Small cell lung cancer 116 (17.0)Non-small cell lung cancer 566 (83.0) Adenocarcinoma 428 (62.8) Squamous cell carcinoma 102 (15.0) Other NSCLCs 36 (5.2)

Genetic mutationa

EGFR mutation positive 187 (27.4) ALK positive 28 (4.1)

Stagea

I-II 20 (2.9) III-IV 662 (97.1)

Cancer metastasisa

� Lymph node metastasis 96 (14.1)

� Distant metastasis 381 (55.9)

Baseline laboratory valuesc

� WBC count ×109 (/L) 7.72 ± 3.74

� Hemoglobin (g/dL) 13.0 ± 1.6

� Platelet count ×109 (/L) 265.4 ± 97.6

� D-dimer (µg/mL) 1.77 ± 4.88

VTEa 71 (10.4)

�DVT alone 48 (7.0)

�PE alone 9 (1.3)

�PE + DVT 14 (2.1)

KRSa

�1 point 536 (78.6)

�2 points 92 (13.5)

�3 points 45 (6.6)

�4 points 9 (1.3)

�5 points 0 (0.0)

an (%), bMedian (range), cMean±SD

10

1.3.2� VTE ȌȈ�d[ďı

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11

Table 3� VTE ȌȈɇ4˔ȌȈɇ7�!IɠŏȏɐƝ8NJʝ

an (%), bMean±SD Values determined by Student’s t-test, Fisher’s exact test, or Mann-Whitney U-test. ALK, anaplastic lymphoma kinase; BMI, body mass index; EGFR, epidermal growth factor receptor; WBC, white blood cell

VTE non-VTE(n=71) (n=611)

Age (years)b 64.5 ± 10.8 66.0 ± 10.1 0.252

�≥ 65 yearsa 42 (59.2) 375 (61.4) 0.897

Sex (male)a 43 (60.6) 406 (66.4) 0.426

BMI (kg/m2)b 22.5 ± 3.5 22.2 ± 3.3 0.672

�≥ 25 (kg/m2)a 20 (28.2) 121 (19.8) 0.163

�≥ 35 (kg/m2)a 0 (0.0) 1 (0.002) 1.000

Comorbiditiesa

� Cardiovascular disease 3 (4.2) 48 (7.9) 0.346

� Diabetes mellitus 8 (11.3) 121 (19.8) 0.107

� Hypertension 30 (42.3) 205 (33.6) 0.232

� Dyslipidemia 12 (16.9) 85 (13.9) 0.470

� Chronic pulmonary disease 11 (15.5) 94 (15.4) 1.000

Smokinga 45 (63.4) 439 (71.8) 0.211

Surgerya 16 (22.5) 116 (19.0) 0.427

ECOG performance statusa

0-1 56 (78.9) 522 (85.4) 0.158 2-4 15 (21.1) 89 (14.6) 0.158

Cancer typea

Non-small cell lung cancer 69 (97.2) 497 (81.3) 0.002 Adenocarcinoma 54 (76.1) 374 (61.2) 0.019 Squamous cell carcinoma 10 (14.1) 92 (15.1) 0.863

Genetic mutationa

EGFR mutation positive 25 (35.2) 162 (26.5) 0.203 ALK positive 1 (1.4) 27 (4.4) 0.346

Stagea

I-II 3 (4.2) 17 (2.8) 0.462 III-IV 68 (95.8) 594 (97.2) 0.462

Cancer metastasisa

� Lymph node metastasis 6 (8.5) 90 (14.7) 0.204

� Distant metastasis 39 (54.9) 342 (56.0) 0.800

Baseline laboratory valuesa

� WBC count > 11 × 109 (/L) 18 (25.4) 65 (10.6) 0.001

� Hemoglobin < 10 (g/dL) 4 (5.6) 21 (3.4) 0.312

� Platelet count ≥ 350 × 109 (/L) 13 (18.3) 87 (14.2) 0.371

� D-dimer ≥ 1.44 (µg/mL) 27 (38.0) 112 (18.3) <0.0001

ALK, anaplastic lymphoma kinase; BMI, body mass index; EGFR, epidermal growth factorreceptor; WBC, white blood cell

an (%), bMean±SDValues determined by Student’s t-test, Fisher’s exact test, or Mann-Whitney U-test.

Parameter p-value

12

Table 4� ƙƩ¤Ɏ�NŬɊ7�!I VTE ȌȈ�d[7˃(IĤĢʽɸƯ

ȾƱ

BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cell

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I Receiver Operating Characteristics Curve ɸƯ

� � AUC: area under the curve

Parameter Odds ratio 95% Confidence interval p-value

BMI ≥ 25 (kg/m2) 2.02 1.06-3.72 0.032Diabetes mellitus 0.47 0.17-1.05 0.068ECOG performance status ≥ 2 1.01 0.46-2.07 0.984Non-small cell lung cancer 3.13 1.32-9.23 0.007

WBC count > 11 × 109 (/L) 2.31 1.11-4.61 0.026D-dimer ≥ 1.44 (µg/mL) 2.73 1.49-4.99 0.001

BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cell

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13

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14

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15

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16

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18

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Table 5� ��|O��ÇɭŽ�ɇ4ž�NɩÇɭŽ�ɇ8ŬɊɐƝ

a) n (%), b) Median (range), c) Mean±SD, 1) Fisher's exact test, 2) Mann-Whitney U-test ALK: anaplastic lymphoma kinase, ALT: alanine aminotransferase, AST: asparatate aminotransferase, BMI: body mass index, CrCl: creatinine clearance, DVT: deep vein thrombosis, EGFR: epidermal growth factor recepter, NSCLC: non-small cell lung cancer, PE: pulmonary embolism, SCLC: small cell lung cancer, SCr: serum creatinine, TKI: tyrosine kinase inhibitor, VTE: venous thromboembolism

WF�TKI WF�non-TKI TKI�WF non-TKI�WF(n = 14) (n = 20) (n = 16) (n = 13)

Age (years)b) 66.0 (40-82) 68.5 (43-76) 0.756 1) 65.0 (36-82) 67.0 (43-76) 0.689 1)

Sex (male)a) 6 (42.3) 12 (60.0) 0.487 1) 5 (31.3) 7 (53.8) 0.285 1)

Weight (kg)c) 61.0 ± 9.4 65.3 ± 18.1 0.423 2) 55.8 ± 12.0 55.6 ± 18.6 0.276 2)

BMI (kg/m2)c) 23.4 ± 3.3 24.7 ± 5.6 0.452 2) 22.5 ± 3.6 22.1 ± 5.6 0.476 2)

ECOG performance statusa)

0-2 14 (100.0) 20 (100.0) 1.000 1) 14 (87.5) 13 (100.0) 0.484 1)

3-4 0 (0.0) 0 (0.0) 1.000 1) 2 (12.5) 0 (0.0) 0.484 1)

Cancer typea)

SCLC 0 (0.0) 1 (5.0) 1.000 1) 0 (0.0) 1 (7.7) 1.000 1)

NSCLC 14 (100.0) 19 (95.0) 1.000 1) 16 (100.0) 12 (92.3) 1.000 1)

Adenocarcinoma 14 (100.0) 12 (60.0) �0.05 1) 16 (100.0) 11 (84.6) �0.05 1)

Squamous cell carcinoma 0 (0.0) 5 (25.0) 0.063 1) 0 (0.0) 1 (7.7) 0.565 1)

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Gene mutationa)

EGFR mutation-positive 8 (57.1) 3 (15.0) �0.05 1) 12 (75.0) 2 (15.4) �0.01 1)

ALK-positive 4 (28.6) 0 (0.0) �0.05 1) 2 (12.5) 0 (0.0) 0.484 1)

VTEa)

�PE�DVT 6 (42.3) 8 (40.0) 0.729 1) 2 (12.5) 6 (46.2) 0.125 1)

PE alone 0 (0.0) 3 (15.0) 0.301 1) 6 (37.5) 1 (7.7) 0.214 1)

DVT alone 8 (57.1) 9 (45.0) 0.503 1) 8 (50.0) 6 (46.2) 0.718 1)

Baseline laboratory valuesc)

�AST (IU/L) 27.9 ± 19.6 22.0 ± 10.0 0.201 2) 21.1 ± 4.3 22.7 ± 10.3 0.498 2)

ALT (IU/L) 27.3 ± 16.0 23.1 ± 11.0 0.189 2) 16.6 ± 6.6 18.1 ± 11.7 0.685 2)

SCr (mg/dL) 0.72 ± 0.21 0.65 ± 0.17 0.358 2) 0.79 ± 0.20 0.67 ± 0.21 0.156 2)

CrCl (mL/min) 84.1 ± 35.4 104.0 ± 39.6 0.248 2) 84.1 ± 35.4 90.6 ± 30.3 0.381 2)

ALK: anaplastic lymphoma kinase, ALT: alanine aminotransferase, AST: asparatate aminotransferase, BMI: body mass index, CrCl: creatinine clearance, DVT:deep vein thrombosis, EGFR: epidermal growth factor recepter, NSCLC: non-small cell lung cancer, PE: pulmonary embolism, SCLC: small cell lung cancer, SCr:serum creatinine, TKI: tyrosine kinase inhibitor, VTE: venous thromboembolism

p value p value

a) n (%), b) Median (range), c) Mean±SD1) Fisher's exact test, 2) Mann-Whitney U-test

24

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25

Table 6� ��|O��ÇɭŽ�ɇ7�!I PT-INR Ģæʽ���|O��

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[lt} 1.0 3�0-�PT-INR �ƚŞ8 WF Ž�ʽ9 TKI˨WF ɇ3 12 ý

/16 ý˥75.0ˤ �˦non-TKI˨WF ɇ3 4 ý /13 ý˥30.8ˤ˦3ǟʽ�6%J2

�-�TKI˨WF ɇ7�!I WF Ž�ʽ9 WF ŁÉƜ 2.6�1.0 mg/day�WF

ŁÉ 7 ƙªˆ8 PT-INRpost ǡĶŞ39 1.6�1.5 mg/day 4Ƥů7ǟŃ&2

�-˥p˫0.01 �˦�Ɩ�non-TKI˨WF ɇ7�!I WF Ž�ʽ9 WF ŁÉƜ

2.7�0.6 mg/day�PT-INRpost ǡĶŞ9 2.8�0.8 mg/day 3�HƤů6ʼn9ʄ

CGJ6�0-�Òɬ9 TKI˨WF ɇ 6 ý /16 ý˥37.5ˤ �˦non-TKI˨WF

WF�TKI(n = 14)

WF�non-TKI(n = 20)

p value

PT-INRbaselineb) 1.96 (1.28-2.94) 1.95 (1.33-2.61) 0.952

PT-INRmaxb) 4.19 (2.70-5.90) 2.37 (1.40-3.56) �0.001

ΔPT-INRb) 2.23 (0.61-3.85) 0.42 (0.03-1.29) �0.001

WF dose at the baseline (mg/day)c) 3.71 ± 1.61*** 3.23 ± 1.26 0.329

WF dose in the presence of anticancer drug (mg/day)c) 0.79 ± 1.35*** 3.00 ± 1.22 �0.001

Number of patients (%) with a reduction of WF dosea) 14 (100.0) 5 (25.0) �0.001

Bleeding incidence (%)a) 6 (42.9) 3 (15.0) 0.228

a) n (%), b) Median (range), c) Mean±SD�Comparison between 2 groups: Mann-Whitney U-test*** P < 0.001 Comparison of the WF dose before and after combining anticancer drugs: Wilcoxon signed-rank testΔPT-INR�PT-INRmax minus PT-INRbaselineTKI group drugs: afatinib (n=3), alectinib (n=1), crizotinib (n=3), erlotinib (n=3), gefitinib (n=4)non-TKI group regimens: AMR (n=1), CBDCA+PTX (n=3), CDDP+PEM (n=7), DTX (n=4), GEM+CPT-11 (n=2),Nivolumab (n=1), PEM (n=2)Abbreviations: AMR: amrubicin, CBDCA: carboplatin, CDDP: cisplatin, CPT-11: irinotecan, DTX: docetaxel, GEM:gemcitabine, PEM: pemetrexed, PT-INR: prothrombin time-international normalized ratio, PTX: paclitaxel, TKI: tyrosinekinase inhibitors, WF: warfarin

26

ɇ 2 ý /13 ý˥15.4ˤ˦7ȌǶ&-�

Fig. 7� ž�NɩÇɭŽ�ɇ7�!I PT-INR Ģæʽ ˧˧˧p < 0.001� Mann-Whitney U-test ΔPT-INR˪PT-INRpost minus PT-INR0

Table 7� ž�NɩÇɭŽ�ɇ7�!I PT-INR Ģæʽ���|O��Ž�

ʽ�ÒɬȌǶǴ

a)

n (%), b) Median (range), c) Mean±SD� Comparison between 2 groups: Mann-Whitney U-test ** p < 0.01 Comparison of the WF dose at the baseline and after PT-INR measurements: Wilcoxon signed-rank test ΔPT-INR�PT-INRpost minus PT-INR0 TKI group drugs: afatinib (n=3), alectinib (n=2), crizotinib (n=2), erlotinib (n=4), gefitinib (n=3), osimertinib (n=2) non-TKI group regimens: AMR (n=1), CBDCA+PEM (n=1), CBDCA+PTX (n=1), CDDP+PEM (n=4), DTX (n=4), GEM+CPT-11 (n=1), PEM (n=1) Abbreviations: AMR: amrubicin, CBDCA: carboplatin, CDDP: cisplatin, CPT-11: irinotecan, DTX: docetaxel, GEM: gemcitabine, PEM: pemetrexed, PT-INR: prothrombin time-international normalized ratio, PTX: paclitaxel, TKI: tyrosine kinase inhibitors, WF: warfarin

TKI�WF(n = 16)

non-TKI�WF(n = 13)

p value

PT-INR0b) 1.10 (1.01-1.21) 1.09 (0.96-1.33) 0.793

PT-INRpostb) 3.06 (1.11-8.49) 1.89 (1.11-3.52) �0.001

ΔPT-INRb) 2.18 (0.10-7.46) 0.68 (0.02-2.35) �0.001

WF dose at the baseline (mg/day)c) 2.56 ± 1.04** 2.68 ± 0.58 0.692

WF dose after PT-INRpost measurement (mg/day)c) 1.58 ± 1.52** 2.75 ± 0.82 �0.01

Number of patients (%) with a reduction of WF dosea) 12 (75.0 ) 4 (30.8) �0.01

Bleeding incidence (%)a) 6 (37.5) 2 (15.4) 0.220

a) n (%), b) Median (range), c) Mean±SD�Comparison between 2 groups: Mann-Whitney U-test** P < 0.01 Comparison of the WF dose at the baseline and after PT-INR measurements: Wilcoxon signed-rank testΔPT-INR�PT-INRpost minus PT-INR0TKI group drugs: afatinib (n=3), alectinib (n=2), crizotinib (n=2), erlotinib (n=4), gefitinib (n=3), osimertinib (n=2)non-TKI group regimens: AMR (n=1), CBDCA+PEM (n=1), CBDCA+PTX (n=1), CDDP+PEM (n=4), DTX (n=4),GEM+CPT-11 (n=1), PEM (n=1)Abbreviations: AMR: amrubicin, CBDCA: carboplatin, CDDP: cisplatin, CPT-11: irinotecan, DTX: docetaxel, GEM:gemcitabine, PEM: pemetrexed, PT-INR: prothrombin time-international normalized ratio, PTX: paclitaxel, TKI: tyrosinekinase inhibitors, WF: warfarin

ΔP

T-IN

R�

����

�n = 13�� �n = 16�� �n = 3�� �n = 4�� �n = 3�� �n = 2�� �n = 2�� �n = 2��

0

1

2

3

4

5

6

7

8

non-TKI�WF TKI�WF Gefitinib Erlotinib Afatinib Osimertinib Crizotinib Alectinib

Fig. 2�Changes in PT-INR in groups receiving anticancer drugs (TKI or non-TKI)�and additionally started on warfarin

���P < 0.001�Mann-Whitney U-test��PT-INR�PT-INRpost minus PT-INR0�

27

� ˥a˦ɇ�˥ b˦ɇÌ7ž�NɩµǽŞ7ɋǀɔ˥AST�ALT�P�}��

˥albumin: Alb˦˦ Eəǀɔ˥SCr�[�Plt�[�P��d˥creatinine

clearance: CrCl˦˦ 8ŭæ9ʄCGJ6�0-�@-�PT-INR ĢæʽʁºƦ

˂Í7��2ʻȳ6Čþ��ȉȈDZ8ȌǶDʄCGJ6�0-�Òɬ8-

C�ʗɬǷʠɬMťɳ4&-Ȉ·� non-TKI˨WF ɇ3 1 ·ʄCGJ-�

1.4� ɉĽ

� ¥Ď�Ŷ�9 WF 8žÐĒäƱ7ò?(ž�Nɩ8ř˘71�2ŞKÿ

�7ʉƲ&-�ƩșȨ39 WF 7FI VTE Ǐȋ�Ɨɭ%J-Ɏ�NŬɊ7

��2�TKI µǽɇ4 non-TKI µǽɇ8 PT-INR ĢæʽMNJʝ&�˥ a˦8

WF ÇɭŽ�ɇ3D˥b˦8ž�NɩÇɭŽ�ɇ3D TKI µǽɇ3Ƥů7

PT-INR ��ƚ(I#4MȜ&-�@-�WF Ž�ʽMǟʽ&-Ȉ·9˥a˦

WF+TKI ɇ 14 ý˥100.0ˤ �˦WF˨non-TKI ɇ 5 ý˥25.0ˤ �˦˥ b˦TKI˨

WF ɇ 12 ý˥75.0ˤ �˦non-TKI˨WF ɇ 4 ý˥30.8ˤ˦4 TKI µǽɇ3 WF

8ǟʽȈ·�Ĥ ʄCGJ-#4�G�TKIs 4 WF µǽƜ79 WF Ž�ʽ

8ǟʽMɉų(Iťɳ��I#4�ȜĈ%J-��Ɩ�non-TKI ɇ39 WF

ÇɭŽ�ɇ3Dž�NɩÇɭŽ�ɇ3DµǽÙŞ8 WF Ž�ʽ7Ƥů6Ģ

å9ʄCGJ6�0-�@-�TKI µǽɇ39ÒɬR��q8ȌǶ�ˡ˜

ő3ʄCGJ-�Òɬ9 non-TKI ɇ 1 ý3 2 ì°ª�8ʗɬǷʠɬMťɳ

4(IĥÒɬ�ʄCGJ-ªģ9(=2ˢÒɬEȑ�Òɬ�ǘæȯÒɬ6

58łÒɬ3�0-��NŬɊ39˔�NŬɊ4NJʝ&2Òɬ�d[�ˡ

6)�WF 7FIžÐĒȋǑƗɭ�39 TKIs 8µǽ7FHÒɬ�d[�%

G7�ƚ(I#4��ǡ%JI-C�çȋş�Ɋò;ŬɊɡʛ7FIÒɬ

�tj��\Mɭ�#4�ʻɳ4ɉ�GJI�

28

� ǶĖ�Ɏ�NǏȋ7ǽ�GJI TKIs 9^|Qlt}�T��lt}�

P|Olt}�Vb��lt}�[�ilt}�P�[lt}�f�lt

}����lt}8 8 ɩÛ3�I�^|Qlt}�T��lt}� WF 8

žÐĒäƱMĠŖ(I#49 WF 8ǝ¨Ɠơ7ɼʞ%J2�I� 37)�^|

Qlt}�T��lt}ªģ8 TKIs 4 WF 8ɩǯ˂ȕ¡´ǽ71�28ĝ

Ă9Ń6� 38-42)�ƩșȨ39�Ȉ·Ƒ9Ń6��P|Olt}�Vb��

lt}�[�ilt}�P�[lt}4 WF Mµǽ&-ˍ8 PT-INR Ģæ

ʽMȜ(#4�3�-�¥Ş�WF 8žÐĒäƱ7ò?(ù TKIs 8ř˘M

ʁº(I-C79�WF Ž��7 TKIs �ˁĮ460-Ȉ·MĿʏ4&2

WF-TKIs µǽÙŞ8 PT-INR MNJʝ(IȈ·8%G6IʉƲ�ťɳ3�I

4ɉ�I�

� ƩșȨ8șȨˇȃ9��Ȉ·Ƒ8Ń6�ìƗɽ8ŞKÿ�ɷĽșȨ3�

I#4��_�~�RP�dE˟�8Ȧ˞�P�_��Ɗóʽ65�PT-INR

8Ģå7ř˘M��Iďı71�2èÓ6ƸɻMɭ�2�6�#4�

�CYP2C9 E WF 8j�^mqɪȎ3�I VKORC1 8ʳ­ıĚ4 PT-INR

�ƚ48˃ʨū71�2ƸɻMɭ02�6�#4�Ƅ"GJI�@-�Ʃ

șȨ39 TKI ɇ�non-TKI ɇ7ɱƑ8ɩÛEǏȋ�Ā@J2�I#4�G�

¥Ş9ùɩÛEǏȋ$47 PT-INR 8Ģå71�2Ƹɻ�ťɳ4ɉ�I�

� ƩƸɻ7FH�WF 4 TKIs 8Ž�˚Ő7˃LG)�2 ÛµǽƜ9 TKIs

ªģ8ž�NɩMµǽ&-Ğú4NJʝ&�PT-INR 8�ƚ�ĥ��#4�Ȝ

Ĉ%J-�@-�TKIs 4 WF 9µǽ(I4 WF 8žÐĒäƱMĠŖ(Iɩ

ǯ˂ȕ¡´ǽ�ʘ#Iöɔū��H�Òɬ�d[Dˡ@I#4�ȜĈ%J

-�WF4 TKIsµǽƜ9 WFŽ�ʽ8ǟʽMɉų(Iťɳ��I4ɉ�I�

29

Ȭ 2Ȱ� ��|O��4l�b�Ys�g˅ĹɩµǽÙŞ8NJʝ 43,44)

�

� Ȭ 2 ʸ8Ȭ 1 Ȱ7��2�WF 4 TKIs 8µǽ7FH PT-INR ��ƚ(I

öɔū�ȜĈ%J-�WF 8ǝ¨Ɠơ79^|Qlt}ET��lt}8

µǽ7FIɬǙÐĒɔ8Ģå7èÓǓů&6�GŽ�(I#44ɼʞ%J

2�I� 37)�ȕ¡´ǽ8˜ő�ȥő�ȌǶƜƦ71�29ƛG�7602

�6��@-�ǝ¨Ɠơ7ȕ¡´ǽ7˃(Iɼʞ86� TKIs 7��2D

WF 8žÐĒäƱ7ř˘Mò?(öɔū��I�&�&�WF 8žÐĒäƱ

7 TKIs �ò?(ř˘71�28ĝĂ9Ń6 �+8>4N5�Ȉ·ĝĂ

3�I˥Table 8˦ 38-42)�+#3�ƩșȨ9 WF 8žÐĒäƱ7ř˘Mò?

( TKIs 8ƀÒ4�WF 4 TKIs µǽˁĮÙŞ8 PT-INR Ģå71�2ʉƲ&

-�

Table 8� ��|O��4l�b�Ys�g˅Ĺɩ8ɩǯ˂ȕ¡´ǽ7˃

(IƓdzƺɳ

CLL, Chronic Lymphocytic Leukemia; CML, Chronic Myelogenous Leukemia; HCC, Hepatocellular

carcinoma; NSCLC, non-small cell lung cancer

TKIs Patients Cancer type WF dose TKIs dose Change of

PT-INR Research

design References

Gefitinib Japanese NSCLC 1.5-5.0 mg/day

250 mg/day

1.5-2.5 → 1.5-6.0

retrospective study (n=12)

Arai S, et al. Int J Clin Oncol. 14: 332-336 (2009).

Erlotinib Caucasian, 47 years, Male NSCLC 2.5

mg/day 150

mg/day 2.6 → 9.1 case report Thomas KS, et al. Am J Health

Syst Pharm. 67: 1426-1429 (2010).

Crizotinib Japanese, 74 yaers, Female NSCLC 2.0

mg/day - 2.6 → 3.65 case report Kubomura Y, et al. J Nippon Med Sch. 84: 291-293 (2017).

Regorafenib Japanese, 76 years, Male

Colorectal cancer

2.0 mg/day

120 mg/day 1.3 → 6.4 case report Kitade H, et al. J Pharm Health

Care Sci. 8: 15 (2016).

Sorafenib

Caucasian, 70 years, Male HCC 36.0

mg/week 200

mg/day 2.8 → 39.5 case report Moretti LV, et al. Am J Health Syst Pharm. 66: 2123-2125 (2009).

Japanese, 60 years, Male HCC 2.0

mg/day 600

mg/day 2.0 → 6.3 case report Shiozawa K, et al. Gan To Kagaku Ryoho. 38: 1713-1715 (2011).

Bosutinib Caucasian, 84 years, Male CLL 5.0

mg/day 300

mg/day 1.6-4.6 → >15 case report Chintakuntlawar AV, et al.

Leukemia & Lymphoma. 55: 2213-2214 (2014).

Imatinib Caucasian CML - 400 mg/day

None of patients showed

abnormal PT-INR

retrospective study (n=8)

Breccia M, et al. Leukemia Research. 34: e224-e225 (2010).

CLL, Chronic Lymphocytic Leukemia; CML, Chronic Myelogenous Leukemia; HCC, Hepatocellular carcinoma; NSCLC, non-small cell lung cancer�

18

30

2.1� ȓȏ

�WF 4^|Qlt} /T��lt}µǽƜ7�!I PT-INR �ƚ8˜ő�

ȥő�ȌǶƜƦMʁº(I�

�WF 8žÐĒäƱ7ř˘Mò?( TKIs 8ƀÒMȓȏ4&�̂ |Qlt}

/T��lt}ªģ8 TKIs4 WFµǽƜ7�!I PT-INR<8ř˘Mʁº(

I�

2.2� ƖǑ

2.2.1� ĿʏŬɊ

� 2009 ō 1 ƣ�G 2017 ō 3 ƣ8Ʀ˂7ËȒʐĐǑ¤�NșȨ¬Ƥƛȇˈ

7��2�WF 4 TKIs Mµǽ&-�NŬɊMĿʏ4&�ŞKÿ�ɷĽșȨ

Mɭ0-�ʲſĜǣ9 TKIs µǽÙ7 WF Ž�ʽ4 PT-INR �Ń6 4D 7

ƙª��Ķ3�0-˥Ōę�20ˤªÍ 45)˦ŬɊ4&-�6��WF 7Çɭ

&2 TKIs Mƥǽ&2�-ŬɊ�TKIs µǽˁĮƜ8 WF Ž�ʽ��ƛ3�

IŬɊ�TKIs µǽŞ7 WF Ž�ʽ�Ġʽ460-ŬɊ�PT-INR ǡĶMɭ

02�6�ŬɊ�TKIs µǽŞ7 AST/ALT �ĜǣÀ�ˇ8 2 ¿ª�460

-ŬɊ�TKIs µǽŞ7 SCr ���d�R�8 1.5 ¿ª�460-ŬɊ�

Appendix 1 7Ȝ%J2�I WF 8žÐĒäƱ7ĢåMò?(öɔū8�I

59 ɩÛ8ƕɵʥáEŽ�ʽ8ĢƠ�6%J-ŬɊMˉģ&-�ƩșȨ9�

ËȒʐĐǑ¤�NșȨ¬çijȷșȨÁǸľƲįƬ8ŻʄMŠ2ķƗ&-

˥2016-1049 �˦

2.2.2� ʉƲƖǑ

� șȨĿʏɊ71�2��ɼ8ɠŏŮĝM˒ıW�obdo�FHóŠ&

31

-�ōˣ�ū×�ʛˀ�³ʻ�BMI�³ɯ˕ȧ�PS�ƘŜdž�úµȈ��

NȦ�ɠŏȇƦ�ȼɅĚ�æijȋǑdž�WF ʱŧȆŬ�WF Ž�ʽ�ɠŏƸ

ƲÀ˥ɋǀɔ�əǀɔMĀB �˦WF E TKIs 4ȕ¡´ǽMʘ#(öɔū8

�IµǽɩÛ4{j�� K ɰÛ@-9ÐĒďıɰÛ¶ǽ8ƤǬ�TKIs ƥǽ

7FIƤĹ�ʏ�˟�Ɗóʽ�Čþ��ȉ658ǘæčȈDZ4ÒɬȈDZ8

ƤǬMʉƲ˙ȓ4&-�

2.2.3� žÐĒäƱ8ʁº

1˦ĿʏɩÛ

�WF ǝ¨Ɠơ7ɩǯ˂ȕ¡´ǽ7˃(Iɼʞ8�I^|Qlt} /T��

lt}MĿʏɩÛ4&-�

�2017 ō 3 ƣ@37Ʃʶ3ʄö%J-ª�8 TKIs˥18 ɩÛ˦MĿʏɩÛ

4&-�

Afatinib, Alectinib, Axitinib, Bosutinib, Ceritinib, Crizotinib, Dasatinib,

Imatinib, Lapatinib, Lenvatinib, Nilotinib, Osimertinib, Pazopanib, Regorafenib,

Ruxolitinib, Sorafenib, Sunitinib, Vandetanib

2˦žÐĒäƱ8ƃƽ

� žÐĒäƱ8ƃƽ4&2 PT-INR Mǽ�-�TKIs µǽÙ8 WF ǏȋƦ˂

M��d�R�4&���d�R�8 PT-INR ŌęÀM PT-INRbaseline 4

ĶɈ&-�PT-INRbaseline 9ü�8 WF Ž�ʽMŽ��7ǡĶ%J- 3 Ď

ª�8 PT-INR 8Ōę4&�TKIs µǽŞ 3 �ƣM PT-INR Ģå8ʁºƦ˂

4&2ɽĶ&- 46)�PT-INR 8Ĝǣȱđ� 1.00�0.2045)3�I-C�TKIs

µǽŞ7 PT-INR � PT-INRbaseline FHD 20ˤMʙ�2�ƚ&-ĞúM

32

WF 8´ǽĠŖ4&-�@-�PT-INR Ģå�µǽÙ4NJʝ&��20ˤªÍ

3�0-Ğú9Ģå6&4&�TKIs µǽŞ8ʁºƦ˂�7�!I PT-INR

ƢĥÀM PT-INRmax 4ĶɈ&-˥Fig. 8 �˦

Fig. 8� ��|O��4l�b�Ys�g˅ĹɩµǽÙŞ7�!I PT-INR

8ĶɈ4žÐĒäƱ8ʁº

3˦PT-INR �ƚ8ȥő = PT-INRmax˩PT-INRbaseline

4˦PT-INR �ƚ8ȌǶƜƦ

� WF 4 TKIs MµǽŞ7 PT-INRbaseline 4NJʝ&�PT-INR �ÕC2 20ˤ

Mʙ�-�ƚMȜ(@38Ʀ˂4&-�

5˦Time in therapeutic range˥TTR˦

� TTR˥ˤ˦ˬ˥PT-INR ǏȋȓƽěÍƦ˂˩PT-INR ǡĶƦ˂˦×100

TTR 9 Rosendaal Ǒ 47) Mǽ�2µǽÙŞ 3 �ƣ˂8ÀMȮÒ&-�PT-INR

8Ǐȋě9 PE@-9 DVTŬɊ7Ŀ&29Ʃʶ8XRr�R�3ƇĪ%J

2�I 1.5-2.548)� 4&�70 DžƨǢ8ŤŷȺåEɘƶğ9 2.0-3.049,50)�70 Dž

ª�8Ğú9 1.6-2.649)4&-�

○-���;|.?�PT-INR �TKIs�H+|PT-INRo20��Zmt�3�Prt���WFH�)

○PT-INR�3|Q( fPT-INR�3F� � PT-INRmax / PT-INRbaseline�

○PT-INR�3|LG58 fPT-INRbaseliney@[rgPT-INRo��w20��Zmt�3�Ps~x|8_�

0

0.5

1

1.5

2

2.5

3

01.05.12 01.06.12 01.07.12 01.08.12 01.09.12 01.10.12 01.11.12 01.12.12 02.01.12

PT-

INR�

TKIs �

PT-INRbaseline�−20% �

+20% �

B]�

���� �� �

ü PT-INR:±20����

ü ��7������

�����

WF dose �

f� f�

f� f�

f� f�

f� f�

f� f�

f� f�

f� f�

f� f�

PT-INRmax �

PT-INR�3LG58�

33

2.2.4� ȿɺɸƯ

� ƑÀ9�ħÀ˥ƢłÀ–ƢĥÀ˦D& 9ŌęÀ�ƽǣÂʼn3Ȝ&-�

TKIs µǽÙŞ8 PT-INR�WF Ž�ʽ�TTR 8�ħÀ8NJʝ9 Wilcoxon 8

ȫø¨˚°ƸĶMǽ��ƤůNjǣ9 0.05 7ɽĶ&-�ȿɺɸƯh|q9

JMP® PRO ver.12˥SAS Institute Japan Ȟ˦Mǽ�-�

2.3� ȾƱ

2.3.1� ŬɊɐƝ

2.3.1.1 ^|Qlt} /T��lt}

� ʉƲƦ˂�8 WF ƥǽŬɊ9 112 ý3�^|Qlt}ɇ˥G ɇ˦11 ý

˥9.8ˤ �˦T��lt}ɇ˥E ɇ˦10 ý˥8.9ˤ˦8ŬɊ� WF MüƜ7ƥ

ǽ&2�-�WF 7Çɭ&2 TKIs Mƥǽ&2�-ŬɊ 4 ý�µǽˁĮƜ8

WF Ž�ʽ /PT-INR ��ƛ3�0-ŬɊ 2 ý�µǽÙ8 WF Ž�Ʀ˂� 7

ƙƨǢ3�IŬɊ 2 ýMˉģ&�G ɇ 6 ý�E ɇ 7 ýMĿʏŬɊ4&-˥ Fig.

9 �˦

Fig. 9� ��|O��4^|Qlt}�F;T��lt}8ȕ¡´ǽʉƲ

7�!I_��qʲſ

7

Data analysis¯Gefitinib¬n=6­/Erlotinib¬n=7­�

Patients taking WF¬n=112­�

Excluded Patients ©preceding treatment with TKIs¬n=4­ ©WF treatment duration of less than 7 days in the baseline phase¬n=2­ ©missing data for WF dose and PT-INR¬n=2­

Patients combining Gefitinib/Erlotinib with WF¬n=12/n=11­�

34

� ��d�R�8ŬɊɐƝ4žÐĒȋǑ8ʃȺM Table 9 7Ȝ&-�Ŀʏ

ŬɊ 13 ·9(=2˔łȺɑɎ�N3�0-�G ɇ8ōˣ�ħÀ9 68 Dž˥ ȁ

/ī :2 ý /4 ý �˦E ɇ9 62 Dž˥ȁ /ī˪3 ý /4 ý˦3�0-�@-���d�

R�8ɋǀɔ�əǀɔ9DŽŋȱđÍ3�0-�

� ĿʏŬɊ7�!IµǽÙ8Ōę WF Ž�ʽ9 G ɇ3 2.6�0.7 mg/day�E

ɇ3 2.9�1.7 mg/day 3�H�PT-INRbaseline �ħÀ9 G ɇ3 2.1�E ɇ3

1.6 3�0-�

35

Table 9� ��|O��4^|Qlt}�F;T��lt}µǽŬɊ7�

!IɠŏȏɐƝ

Targ

etIN

R ra

nge

1.6

- 2.6

1.5

- 2.5

1.5

- 2.5

2.0

- 3.0

1.5

- 2.5

1.5

- 2.5

1.5

- 2.5

1.6

- 2.6

1.5

- 2.5

1.5

- 2.5

1.5

- 2.5

2.0

- 3.0

1.5

- 2.5

INR

a

2.42

± 0

.23

1.63

± 0

.20

2.31

± 0

.26

2.53

± 0

.22

1.03

± 0

.03

1.93

± 0

.13

1.46

± 0

.11

2.10

± 0

.05

2.28

± 0

.28

1.45

± 0

.10

1.33

± 0

.10

2.12

± 0

.29

1.56

± 0

.18

WF

dose

[wee

kly

dose

]

(mg/

day)

3.5

[24.

5]

3.0

[21.

0]

2.0

[14.

0]

2.0

[14.

0]

3.0

[21.

0]

2.0

[14.

0]

1.5

[10.

5]

3.5

[24.

5]

3.5

[24.

5]

1.0

[7.0

]

2.0

[14.

0]

3.0

[21.

0]

6.0

[42.

0]

Indi

catio

nfo

r WF

Af

PE/C

I

PE Af

PE PE DV

T

Af

DV

T

PE PE CI

DV

T

PS 0 0 0 0 0 1 1 1 1 0 4 1 1

Stag

e

ⅡA Ⅳ Ⅳ Ⅳ Ⅲb Ⅳ Ⅳ ⅡA Ⅳ Ⅳ Ⅳ Ⅳ Ⅰb

Alb

a

(g/d

L)

3.84

± 0

.20

3.64

± 0

.33

3.95

± 0

.08

3.70

± 0

.09

4.33

± 0

.15

3.53

± 0

.05

3.72

± 0

.33

4.12

± 0

.09

3.91

± 0

.11

3.67

± 0

.15

3.31

± 0

.40

3.92

± 0

.04

4.06

± 0

.35

ALT

a

(IU

/L)

35.6

± 1

0.2

19.0

± 5

.3

23.3

± 1

.2

11.6

± 1

.1

28.3

± 4

.6

22.0

± 3

.6

26.7

± 5

.2

19.0

± 2

.7

24.1

± 3

.3

13.2

± 0

.5

47.3

± 1

6.2

13.8

± 1

6.3

22.8

± 4

.5

AST

a

(IU

/L)

85.2

± 1

0.2

23.2

± 6

.6

29.8

± 2

.3

23.0

± 1

.0

21.6

± 2

.0

23.3

± 2

.0

18.0

± 2

.4

58.5

± 4

.6

41.1

± 5

.4

20.2

± 1

.7

25.1

± 7

.6

14.0

± 5

.8

27.6

± 5

.2

CrC

la

(mL/

min

)

59.2

± 9

.3

76.2

± 1

0.4

58.7

± 5

.8

65.1

± 3

.1

80.5

± 1

.3

84.0

± 6

.8

69.8

± 6

.3

64.5

± 1

.7

87.1

± 5

.2

75.8

± 1

.4

98.8

± 6

.5

47.8

± 4

.0

58.7

± 2

.7

Scra

(mg/

dL)

0.68

± 0

.11

0.51

± 0

.06

0.68

± 0

.06

0.92

± 0

.04

0.89

± 0

.01

0.55

± 0

.04

0.64

± 0

.05

0.63

± 0

.01

0.50

± 0

.03

0.66

± 0

.01

0.71

± 0

.04

0.93

± 0

.07

1.16

± 0

.05

BSA (㎡

)

1.51

1.44

1.46

1.64

1.69

1.50

1.44

1.53

1.36

1.62

1.67

1.36

1.69

BW

(kg)

54.8

50.7

50.1

57.2

60.9

52.0

46.3

57.2

50.7

63.1

60.1

41.1

60.9

Sex F F F M M F F F F F M M M

Age 79 75 73 64 55 64 58 79 67 72 56 62 59

Che

mot

hera

py re

gim

en

Gef

itini

b （25

0 m

g/da

y ）

Gef

itini

b （25

0 m

g/da

y ）

Gef

itini

b （25

0 m

g/da

y ）

Gef

itini

b （25

0 m

g/da

y ）

Gef

itini

b （25

0 m

g/da

y ）

Gef

itini

b （25

0 m

g/da

y ）

Erlo

tinib（

150

mg/

day ）

Erlo

tinib（

150

mg/

day ）

Erlo

tinib（

150

mg/

day ）

Erlo

tinib（

150

mg/

day ）

Erlo

tinib（

150

mg/

day ）

Erlo

tinib（

150

mg/

day ）

Erlo

tinib（

150

mg/

day ）

Cas

e

1 2 3 4 5 6 7 8 9 10 11 12 13Tabl

e 1.

Pat

ient

Cha

ract

eris

tics,

Che

mot

hera

py R

egim

ens

and

War

farin

The

rapy

at t

he B

asel

ine.

Abb

revi

atio

ns: A

f, at

rial f

ibril

latio

n; A

lb, a

lbum

in; A

LT, a

lani

ne a

min

otra

nsfe

rase

; AST

, asp

arat

ate

amin

otra

nsfe

rase

; BSA

, bod

y su

rfac

e ar

ea; B

W, b

ody

wei

ght;

CrC

l, cr

eatin

ine

clea

ranc

e; C

I,ce

rebr

al in

farc

tion;

DV

T, d

eep

vein

thro

mbo

sis;

F, f

emal

e; IN

R, i

nter

natio

nal n

orm

aliz

ed ra

tio; M

, mal

e; P

E, p

ulm

onar

y em

bolis

m; P

S, p

erfo

rman

ce s

tatu

s; S

Cr,

seru

m c

reat

inin

e; W

F, w

arfa

rin.

a, M

ean±

SD

36

2.3.1.2 l�b�Ys�g˅Ĺɩ

� ʉƲƦ˂�7 TKIs˥18 ɩÛ˦MŽ�%J2�-ŬɊ9 1,224 ý3�H�

+8�/ 29 ý˥ 2.4ˤ �˦ WF MµǽŽ�%J2�-�WF 7Çɭ&2 TKIs

Mƥǽ&2�-ŬɊ 11 ý�µǽˁĮƜ8 WF Ž�ʽ��ƛ3�0-ŬɊ 2

ý�TKIs µǽŞ7 WF Ġʽ460-ŬɊ 3 ý�µǽŞ PT-INR ǡĶMɭ0

2�6�0-ŬɊ 3 ýMˉģ&�ĜǣMǢ-&- 10 ýMĿʏ4&-�Ŀʏ

ŬɊ 10 ý7Ž�%J2�- TKIs 9 7 ɩÛ3�H�Íɾ9P|Olt} 2

ý�P�[lt} 2 ý�PYblt} 1 ý�[�ilt} 2 ý�yiyt

} 1 ý��`�|St} 1 ý�x�pjt} 1 ý3�0-˥Fig. 10 �˦

Fig. 10� ��|O��4 18 Ȧ8l�b�Ys�g˅Ĺɩȕ¡´ǽʉƲ7

�!I_��qʲſ

Afatinib˥ n=2 ,˦ Alectinib˥ n=2 ,˦ Axitinib˥ n=1 ,˦ Crizotinib˥ n=2 ,˦ Pazopanib˥ n=1 ,˦

Regorafenib˥ n=1˦ , Vandetanib˥ n=1˦

10

Patients combining WF�n=29��

Data analysis�n=10, 7TKIs�

Excluded Patients �Patients not combining WF�n=1,195�

Patients taking TKIs �n=1,224��

Excluded Patients ��receding treatment with TKIs��=11� �missing data for WF dose and PT-INR�n=5� �Patients with increased WF dose after TKIs combined��=3�

Afatinib�n=2�, Alectinib�n=2�, Axitinib�n=1�, Crizotinib�n=2�, Pazopanib�n=1� Regorafenib�n=1�, Vandetanib�n=1��

37

� ŬɊɐƝM Table 10 7Ȝ(�ĿʏŬɊ 10 ·9 PE D& 9 DVT 7Ŀ&

2 WF �ÑƖ%J2�H�+8�/ 1 ý9 PE 4 DVT MüƜ7ȌȈ&-Ȉ

·3�0-�ĿʏŬɊ8ōˣ�ħÀ9 65.5 Dž˥ȁū /īū˪3 ý /7 ý˦3�

H���d�R�8ɋǀɔ9DŽŋȱđÍ3�0-��əǀɔ9 CrCl � 60

mL/min ª�8Ȉ·� 5 ·ʄCGJ-���d�R�8 WF 8ŌęŽ�ʽ9

3.1�1.5 mg/day 3�H�PT-INRbaseline 8�ħÀ9 1.8˥ 1.5-2.4 3˦�0-�

PT-INRbaseline 9 10 ·Ê·3 WF ǏȋěÍ˥PT-INR: 1.5-2.5˦7_�q�

��%J2�-�

38

Table 10� ��|O��4 7 Ȧ8l�b�Ys�g˅ĹɩµǽŬɊ7�!

IɠŏȏɐƝ

Cas

eC

hem

othe

rapy

regi

men

Age

Sex

BW

BS

AS

Cra

CrC

laA

STa

ALT

aA

lba

Sta

geP

SC

ance

r typ

eIn

dica

tion

for W

F W

F do

se

�mg/

day�

�kg�

�m2 �

�mg/

dL�

�mL/

min�

�IU

/L�

�IU

/L�

�g/d

L��m

g/da

y�

1A

fatin

ib�4

0�75

F60

.51.

590.

76 ±

0.0

761

.1 ±

5.0

22.5

± 1

.917

.7 ±

2.0

3.74

± 0

.08

Ⅳ1��

Pul

mon

ary

aden

ocar

cino

ma

PE

1.0

2A

fatin

ib�4

0�68

F50

.01.

340.

51 ±

0.0

483

.8 ±

7.0

26.3

± 1

.915

.5 ±

1.2

3.85

± 0

.05

ⅢA

1��

Pul

mon

ary

aden

ocar

cino

ma

DV

T/P

E2.

5

3A

lect

inib�6

00�

63F

49.6

1.47

1.21

± 0

.07

37.3

± 2

.531

.2 ±

5.2

26.0

± 6

.73.

38 ±

0.1

3Ⅳ

0��

Pul

mon

ary

aden

ocar

cino

ma

PE

2.5

4A

lect

inib�6

00�

56F

68.8

1.70

0.56

± 0

.04

120.

8 ±

8.4

21.3

± 2

.322

.3 ±

5.8

3.50

± 0

.17

IA2��

Pul

mon

ary

aden

ocar

cino

ma

PE

6.0

5A

xitin

ib�1

0�78

M48

.41.

430.

99 ±

0.0

344

.7 ±

1.3

18.7

± 2

.010

.7 ±

1.5

3.72

± 0

.09

Ⅳ0��

Ren

al c

ell c

arci

nom

aD

VT

2.0

6C

rizot

inib�2

50�

62F

49.4

1.45

1.10

± 0

.10

42.0

± 4

.126

.0 ±

4.0

15.7

± 2

.24.

15 ±

0.1

9Ⅳ

0��

Pul

mon

ary

aden

ocar

cino

ma

PE

3.0

7C

rizot

inib�5

00�

61F

46.5

1.47

0.86

± 0

.19

43.0

± 9

.714

.5 ±

2.6

8.0

± 2.

13.

93 ±

0.2

3Ⅳ

0��

Pul

mon

ary

aden

ocar

cino

ma

PE

5.0

8P

azop

anib�8

00�

75F

50.5

1.32

0.89

± 0

.08

48.7

± 4

.124

.6 ±

1.5

15.2

± 1

.03.

34 ±

0.1

5Ⅳ

0��

Ute

rine

sarc

oma

DV

T4.

0

9R

egor

afen

ib�1

20�

74M

59.1

1.86

0.61

130.

520

.7 ±

2.0

16.0

± 2

.13.

85 ±

0.1

2Ⅲ

B0��

Sig

moi

d co

lon

canc

erD

VT

2.0

10Va

ndet

anib�3

00�

43M

74.2

1.74

1.02

± 0

.04

66.5

± 3

.225

.3 ±

1.0

12.1

± 1

.33.

98 ±

0.0

9Ⅳ

0��

Med

ulla

ry c

arci

nom

a of

thyr

oid

DV

T2.

5

Mea

n or

Med

ian

65.5

(43-

78)b

55.7

± 9

.6a

1.54

± 0

.18a

0.85

± 0

.24a

67.8

± 3

3.6a

23.1

± 4

.6a

15.9

± 5

.3a

3.74

± 0

.27a

3.05

± 1

.51a

Abb

revi

atio

n: A

lb, a

lbum

in; A

LT, a

lani

ne a

min

otra

nsfe

rase

; AS

T, a

spar

atat

e am

inot

rans

fera

se; B

SA

, bod

y su

rface

are

a; B

W, b

ody

wei

ght;

CrC

l, cr

eatin

ine

clea

ranc

e; D

VT,

dee

p ve

in th

rom

bosi

s; F

, fem

ale;

M, m

ale;

PE

, pul

mon

ary

embo

lism

; PS

, per

form

ance

stat

us; S

Cr,

seru

m c

reat

inin

e; W

F, w

arfa

rina,

mea

n±S

D, b

, med

ian

(ran

ge)

39

2.3.2 žÐĒäƱ8ʁº

2.3.2.1 ^|Qlt} /T��lt}

� Gɇ�F; Eɇ7�!IWF4 TKIsµǽÙŞ8 PT-INRĢæM Table 11�

Fig. 11 7Ȝ&-�WF 4ù TKIs 8µǽŞ7 G ɇ3 83.3ˤ˥5 ý /6 ý˦��

F; E ɇ3 85.7ˤ˥6 ý /7 ý˦8 PT-INR �ƚ�ʄCGJ-�G ɇ39�

PT-INR �ƚŞ7(=28ŬɊ˥5 ý /5 ý˦3 WF Ž�ʽ9ǟŃ%J2�-

��E ɇ39 3 ý8ŬɊ3 PT-INR �ƚŞD PT-INR �ǏȋěȱđÍ3�0

--C�WF Ž�ʽ�ǟʽ%J-89 50ˤ˥3 ý /6 ý˦8A3�0-�

� µǽÙŞ7�!I PT-INR �ħÀ9 G ɇ3 2.1 �G 3.4˥p˫0.05˦�E ɇ

3 1.6 �G 2.9˥p˫0.05˦7Ƥů7�ƚMȜ&-��ɇ7��2�TKIs µ

ǽŞ7 PT-INRbaseline�G 1.6-1.8¿8 PT-INR�ƚMʄC-�+J7®��

G ɇ39 WF Ž�ʽ�ħÀ9 2.6 mg/day �G PT-INRmax Ş7 1.8 mg/day�

E ɇ39 2.9 mg/day �G 1.8 mg/day <4ǟŃMȜ&-��Ƥů6ʼn9ʄC

GJ6�0-�TKIs µǽÙŞ7�!Iɋǀɔ˥AST�ALT�Alb �˦əǀɔ

˥SCr, CrCl˦79Ƥů6Ģæ9ʄCGJ6�0-�

40

Table 11� ��|O��4^|Qlt}�F;T��lt}µǽŬɊ7�

!I PT-INR �ƚ8˜ő�ȥő�ȌǶƜƦ

aMedian�range��bMean±SD Abbreviations: INR, international normalized ratio; TKIs, tyrosine kinase inhibitors.

Fig. 11� ��|O��4^|Qlt}˥ A; n=6 �˦F;T��lt}˥ B; n=7˦

µǽÙŞ7�!I PT-INR Ģæ

Median and 75% confidence intervals are shown at the left and right of the figure.

Wilcoxon 8ȫø¨˚°ƸĶ

*p < 0.05

Gefitinib (n=6) Erlotinib (n=7)Number of patients (%) showing INR elevation inthe presence of TKIs 5/6 (83.3) 6/7 (85.7)

Number of patients (%) with a reduction of warfarindaily dose in the presence of TKIs 5/5 (100.0) 3/6 (50.0)

2.58±0.66 2.92±1.66

[18.08±4.65] [20.50±11.68]

1.80±1.17 1.80±2.27

[12.30±8.20] [12.50±15.89]

Time (days) a until INR elevation 7 (4-22) 9 (2-62)

INRa during the baseline period 2.12 (1.03-2.53) 1.56 (1.33-2.28)

Maximum INRa in the presence of TKIs 3.35 (1.13-5.22) 2.85 (1.27-3.74)

Post-INR / pre-INR ratioa 1.83 (1.03-2.26) 1.58 (0.89-2.56)

Warfarin daily dose at the baseline (mg/day)b

[weekly dose (mg/week)b]

Warfarin daily dose in the presence of TKIs

(mg/day)b [weekly dose (mg/week)b]

aMedian�range��bMean±SD

Abbreviations: INR, international normalized ratio; TKIs, tyrosine kinase inhibitors.

8

�2������

0

1

2

3

4

5

6

PT-INRbaseline PT-INRmax

PT-

INR�

��

0

1

2

3

4

5

6

PT-INRbaseline PT-INRmax

PT-

INR�

��

�p < 0.05�Wilcoxon��������

A� �B�

PT-INR�� �� � ����

Gefitinib� 5�/6��83.3��� 1.83�1.03-2.26��

Erlotinib� 6�/7��85.7��� 1.58�0.89-2.56��

41

� ^|Qlt}@-9T��lt}4 WF MµǽˁĮ&-Ş8 PT-INR 8

ȽƜĢæM Fig. 12 7Ȝ&-��ɇ8 75ˤª�8ŬɊ�µǽˁĮŞ 2 ʩ˂

ªÍ7 PT-INR �ƚMȜ&-�˥ ȌǶ�ħÀ G ɇ 7 ƙ�E ɇ 9 ƙ �˦2 ý˥ G

ɇ 1ý�F; Eɇ 1ý 9˦ 20ˤMʙ�I PT-INRĢæ9ʄCGJ6�0-�

Fig. 12� ��|O��4^|Qlt}˥ A; n=6 �˦F;T��lt}˥ B; n=7˦

µǽˁĮƜ�G PT-INRmax @38 PT-INR Ƈȣ

� ƩƸɻ7�!IĿʏŬɊ39 PT-INR ǡĶ8˜ő�ˇGJ2�--C�

TKIs µǽÙŞ 3 �ƣ˂8 TTRˤ9 G ɇ 3 ý�E ɇ 4 ý38AȮÒöɔ3�

0-�TTRˤ˥�ħÀ˦9���d�R�Ʀ˂�8 91.1ˤ˥PT-INR ǡĶĎ

Ƒ�ħÀ 4.0˦�G^|Qlt}µǽŞ8 56.3ˤ˥PT-INR ǡĶĎƑ�ħÀ

9.0˦��F;��d�R�Ʀ˂�8 50.6ˤ˥PT-INR ǡĶĎƑ 4.0˦�GT

��lt}µǽŞ8 36.4ˤ˥PT-INR ǡĶĎƑ�ħÀ 5.0˦@3ǟŃMʄC

-˥Table 12, 13˦�

0

1

2

3

4

5

6

0 7 14 21 28 35 42 49 56

PT-

INR�

�day��

Time�day�of the elevation�

9

A� B�

�2������

0

1

2

3

4

5

6

0 7 14 21 28 35 42 49 56 63 70

PT-

INR�

�day��

Time�day�of the elevation�

42

Table 12 � � �|O��4^|Qlt}µǽÙŞ7�!I Time in

therapeutic range

Time within the therapeutic range for 3 months in patients before and after combination

of warfarin with gefitinib.

Table 13 � � �|O��4T��lt}µǽÙŞ7�!I Time in

therapeutic range

Time within the therapeutic range for 3 months in patients before and after combination

of warfarin with erlotinib.

Appendix 2-1. Time in therapeutic range in patients before and after combining

warfarin with gefitinib.

Case TTR (%) number of INR measurements

before after before after

1 91.1 56.3 4 6

2 - - - -

3 66.8 12.2 6 9

4 92.4 58.0 3 10

5 - - - -

6 - - - -

Median�n=3� 91.1 56.3 4.0 9.0

Time within the therapeutic range for 3 months in patients before and after combination

of warfarin with gefitinib. Appendix 2-2. Time in therapeutic range in patients before and after combining

warfarin with erlotinib.

Case TTR (%) number of INR measurements

before after before after

7 - - - -

8 100 34.0 2 5

9 - - - -

10 33.8 61.9 4 3

11 0.0 0.0 4 5

12 - - - -

13 67.4 38.8 4 8

Median�n=4� 50.6 36.4 4.0 5.0

Time within the therapeutic range for 3 months in patients before and after

combination of warfarin with erlotinib.

Appendix 2-1. Time in therapeutic range in patients before and after combining

warfarin with gefitinib.

Case TTR (%) number of INR measurements

before after before after

1 91.1 56.3 4 6

2 - - - -

3 66.8 12.2 6 9

4 92.4 58.0 3 10

5 - - - -

6 - - - -

Median�n=3� 91.1 56.3 4.0 9.0

Time within the therapeutic range for 3 months in patients before and after combination

of warfarin with gefitinib. Appendix 2-2. Time in therapeutic range in patients before and after combining

warfarin with erlotinib.

Case TTR (%) number of INR measurements

before after before after

7 - - - -

8 100 34.0 2 5

9 - - - -

10 33.8 61.9 4 3

11 0.0 0.0 4 5

12 - - - -

13 67.4 38.8 4 8

Median�n=4� 50.6 36.4 4.0 5.0

Time within the therapeutic range for 3 months in patients before and after

combination of warfarin with erlotinib.

43

2.3.2.2 l�b�Ys�g˅Ĺɩ

� ùȈ·8 PT-INR Ģå71�2 Table 14 4 Fig. 13 7Ȝ&-�TKIs 4 WF

8µǽ7FI PT-INR 8 20ˤª�8�ƚ9 10 ·� 10 ·˥100.0ˤ˦7ʄC

GJ�PT-INRmax� VTEǏȋě�ˇ3�I 2.5Mʙ�-ŬɊ9 8 ·˥ 80.0ˤ˦

3�0-�ĿʏŬɊ7�!I PT-INR �ħÀ9 TKIs µǽÙŞ3 1.8 �G 3.1

<Ƥů6�ƚ�ʄCGJ-˥ p˫0.01 �˦@-�PT-INR �ƚǴ8�ħÀ9 1.6

¿3�H�Ƣĥ 1.8 ¿@3 PT-INR ��ƚ&-Ȉ·MʄC-�TKIs µǽŞ

7 PT-INR � 2.5 Mʙ�- 8 ·39Ê·3 WF Ž�ʽ�ǟʽ%J�Ōę WF

Ž�ʽ9µǽÙ 3.1�1.5 mg/day �GµǽŞ 1.6�1.2 mg/day <4ǟʽMʄ

C-˥p˫0.01 �˦TTR ŌęÀ9µǽÙ 78.5ˤ˥PT-INR ǡĶĎƑŌęÀ 4.8

Ď˦4NJʝ&�µǽŞ 60.1ˤ˥PT-INR ǡĶĎƑŌęÀ 7.3 Ď˦4�TKIs

µǽ7FH PT-INR _�q�����ɤ46IÃÿMʄC-�

Table 14� ��|O��4 7 Ȧ8l�b�Ys�g˅ĹɩµǽÙŞ7�!

I PT-INR���|O��Ž�ʽ�Time in therapeutic range

a, mean±SD, b, median (range)

**p < 0.01 as compared with the baseline values

Abbreviation: TTR, time in therapeutic range; PT-INR, prothrombin time-international

normalized ratio; WF, warfarin

baseline after baselinea maximum baseline after

1 Afatinib 1.0 1.0 1.65 ± 0.20 2.40 1.45 41 92.0 87.7

2 Afatinib 2.5 0.0 2.35 ± 0.24 3.12 1.33 2 88.3 38.7

3 Alectinib 2.5 2.0 2.39 ± 0.28 3.25 1.36 32 85.0 52.4

4 Alectinib 6.0 4.0 1.82 ± 0.38 2.70 1.48 3 - -

5 Axitinib 2.0 1.0 1.85 ± 0.35 3.02 1.63 41 100.0 68.1

6 Crizotinib 3.0 2.0 2.27 ± 0.41 4.05 1.78 16 56.5 4.2

7 Crizotinib 5.0 0.0 1.78 ± 0.43 3.24 1.82 11 65.5 47.3

8 Pazopanib 4.0 2.0 2.44 ± 0.04 4.16 1.70 20 44.7 -

9 Regorafenib 2.0 1.0 1.51 ± 0.17 2.56 1.70 6 100.0 82.0

10 Vandetanib 2.5 2.5 1.60 ± 0.12 2.10 1.31 42 74.7 100.0

Mean or Median 3.05 ± 1.51a 1.55 ± 1.21a** 1.83 (1.51-2.44)b 3.07 (2.10-4.16)b** 1.56 (1.31-1.82)b 18 (2-42)b 78.5 ± 19.5a60.1 ± 30.9a

a, mean±SD, b, median (range)

**P < 0.01 as compared with the baseline values

casePT-INR

Abbreviation: TTR, time in therapeutic range; PT-INR, prothrombin time-international normalized ratio; WF, warfarina, mean±SD, b, median (range)

PT-INRmax/baseline ratio

Time (days) untilPT-INR elevation

WF dose (mg/day) TTR (%)

44

Fig. 13� ��|O��4 7 Ȧ8l�b�Ys�g˅ĹɩµǽÙŞ7�!I

PT-INR Ģæ

Median and 75% confidence intervals are shown at the left and right of the figure.

Wilcoxon 8ȫø¨˚°ƸĶ

**p <0.01 between the two groups of PT-INR values

� Fig. 14 7 WF 4ù TKIs µǽŞ8 PT-INR 8ȽƜĢæMȜ&-�PT-INR

�ƚ8ȌǶƜƦ�ħÀ9 18 ƙ˥ 2-42 ƙ 3˦�H�µǽ 1 ʩ˂ªÍ7 PT-INR

�ƚMʄC-Ȉ·9 3 ·˥30.0ˤ �˦µǽ 1 �ƣªÍ38 PT-INR �ƚ9 6

·˥60.0ˤ˦3�0-�TKIs µǽÙŞ7�!Iɋǀɔ˥AST�ALT�Alb �˦

əǀɔ˥SCr, CrCl˦79Ƥů6Ģæ9ʄCGJ6�0-�@-�ÒɬEʻ

ȳ6Čþ��ȉȈDZ8ȌǶ96 �{j�� K ɰÛ�+8§8ÐĒďıɰ

Û8¶ǽDʄCGJ6�0-�

0

1

2

3

4

5

6

PT-INRbaseline PT-INRmax

Afatinib (Case1)

Afatinib (Case2)

Alectinib (Case3)

Alectinib (Case4)

Axitinib (Case5)

Crizotinib (Case6)

Crizotinib (Case7)

Pazopanib (Case8)

Regorafenib (Case9)

Vandetanib (Case10)

**p <0.01 between the two groups of PT-INR values�

�

PT-

INR�

�2������

45

Fig. 14� ��|O��4 7 Ȧ8l�b�Ys�g˅ĹɩµǽˁĮƜ�G

PT-INRmax @38 PT-INR Ƈȣ

0

1

2

3

4

5

0 7 14 21 28 35 42 49 56 63 70 77

Afatinib (Case1)

Afatinib (Case2)

Alectinib (Case3)

Alectinib (Case4)

Axitinib (Case5)

Crizotinib (Case6)

Crizotinib (Case7)

Pazopanib (Case8)

Regorafenib (Case9)

Vandetanib (Case10)

PT-

INR�

Time�day�after the initiation of the different TKIs�

�2������

46

2.4� ɉĽ

ƩƸɻ9 TKIs 8IJĖ�7�!I WF 8žÐĒäƱĠŖ�˔ŋ7˜Ʉ3

�I#4Mķʀ&-ƢÕ8șȨ3�H�^|Qlt}�F;T��lt}

4 WF Mµǽ&-ŬɊ8ȸ 85ˤ� PT-INR �ƚMȜ&-�WF 4T��l

t}µǽ7�!Iȕ¡´ǽ8˜ő7˃&2ʭð7ĝĂ96 �WF 4^|

Qlt}µǽ7�!Iȕ¡´ǽ8ȌǶǴ˥83ˤ˦9�ªÙ7ĝĂ%J-˜

ő˥50ˤ˦FHDˡÀ3�0- 35)�Arai G9 12 ý8Ɏ�NŬɊMĿʏ4

&- WF 4^|Qlt}8µǽŞ 2 ʩ˂ªÍ8 PT-INR Ģå71�2ʉƲ

&- 35)�śG9ĝĂÍ3 PT-INR �ƚ8ĶɈMȜ&2�6�0--C�

PT-INR �ƚ8ĶɈ9Ŷ�˥��d�R�À�G 20ˤª�8 PT-INR �ƚ˦

4ȅ6Iöɔū��I�%G7�ƩʉƲ39 PT-INR �ƚ9 2 ʩ˂ªÍ7 8

ý / 13 ý˥61.5ˤ˦7&�ʄCGJ6�0--C�ɷĽƦ˂�ˀ�˥3 �ƣ

vs 2 ʩ˂˦#4�ʸÓȏ7Ŷ�8șȨ7�!I PT-INR �ƚ8ˡ�ȌǶǴ

7˃�&2�Iöɔū��I4ɉ�GJ-�@-�¥ĎŶ�9^|Qlt

} /T��lt}ªģ8 TKIs � WF 8žÐĒäƱ7ò?(ř˘71�2D

ŞKÿ�7ʉƲ&-�ƩșȨ3Ŀʏ460- 7 ɩÛ71�29 WF 48µ

ǽ7FH 10 ·Ê·3 20ˤª�8 PT-INR �ƚMʄC-#4�G�WF 48

µǽ7FHžÐĒäƱ8ĠŖ�ǝ¨Ɠơȭ7ĝĂ%J2�I^|Qlt}

ET��lt}ªģ8 TKIsDWF48ɩǯ˂ȕ¡´ǽ�IJĖ(IöɔūM

ɴÒ&-�

G ɇ�F; E ɇ7�!I PT-INR �ƚ8ȥő˥PT-INRbaseline �G

60-80ˤĠá˦9ʭð8ĝĂ4˞¯&2�- 35)�ƩșȨ3Ŀʏ460-^

|Qlt} /T��lt}ªģ8 7 ɩÛ 10 ·8 PT-INR �ƚǴ9 1.6 ¿

˥ 1.3-1.8˦3�H�ƩșȨ8^|Qlt}�F;T��lt}7�!I

47

PT-INR �ƚǴ4>?üȭ8�ƚǴMʄC-�ù TKI µǽÙŞ8 WF Ž�

ʽ�ħÀ9 G ɇ 2.6 mg/day �G 1.8 mg/day�E ɇ 2.9 mg/day �G 1.8 mg/day

<4ȸ 30ˤ8ǟŃMȜ&-�@-�^|Qlt} /T��lt}ªģ8 7

ɩÛ39 10 ·� 8 ·˥80.0ˤ˦3 TKIs µǽŞ7 WF 8ǟʽ@-9�ǃ�

6%J2�-�Ōę WFŽ�ʽ9µǽÙ8 3.1�1.5 mg/day�GµǽŞ9 1.6

�1.2 mg/day <4ǟʽ%J2�H�ƩșȨ3Ŀʏ460- 7 Ȧ8 TKIs 4

WFµǽƜ79 WFŽ�ʽ8ǟʽMɉų(Iťɳ��I#4�ȜĈ%J-�

�NșȨ¬ƤƛȇˈăāčÍȢ39��NæijȋǑŁÉƜ79 2 ʩ˂

8ÉˈMɳ(I³Ø7602�I�G ɇ7�!I PT-INR ȽƜƇȣ39�

ƢÕ8 2 ʩ˂3 20ˤMʙ�I PT-INR �ƚMʄC-ŬɊ8�/�2 ý8Ŭ

Ɋ�ʦˈŞ7 4.0 ª�8 PT-INR MȜ&2�-˥ Fig. 12A �˦Éˈ�8 PT-INR

9ʨɀȏ6�ƚMȜ&-��ǡĶ%J- PT-INR À�ǏȋěȱđÍ3�0

-#4�G�WF Ž�ʽ�ʦˈÙ7ǟʽ%J)�ʦˈŞ7ǏȋěMʙ�I

PT-INR �ƚ716�0-öɔū��I�#JG8p�j9�ǏȋěȱđÍ

3 2 18ʨɀ&- PT-INR 8�ƚ�ɷĽ%JIĞú�WF Ž�ʽ8ǟʽMƸ

ɻ(Iťɳ��I#4MȜĈ&2�I��Ɩ�G ɇ�F; E ɇ7Ā@JI

2 ý8ŬɊ9�ƽǣǽʽ8 WF˥2.0 mg/day �F; 3.0 mg/day˦Mƥǽ&2

�-7D˃LG)�TKIsµǽŞ7D PT-INR8�ƚMȜ%6�0-�PT-INR

�ƚMȜ%6�0- 2ý8 PT-INR9 1.0-1.58˂3Ƈȣ&2�I-C�Ŷ�

9#JG8ŬɊ8 WF Ž�ʽ� TKIs ˔IJĖ�7��2D�TKIs IJĖ�7

��2DžÐĒäƱ8ȌǶ�ƛG�76I79 WF Ž�ʽ��ʚ&2�I

���I�9w�_�~�RP�dȭ8öɔū��0-4ɉ�I�

PT-INR �ƚ8ȌǶ@38Ʀ˂˥2 ʩ˂ªÍ˦7˃&29�Ŷ�8ȾƱ

9 Arai G8ĝĂ4üƼ3�0- 35)�&�&�ȌǶ@38Ʀ˂9 G ɇ39

48

4-22ƙ�Eɇ39 2-62ƙ8ȱđ3�H�¾¤˂3ĥ�6Ģå�ʄCGJ-�

PT-INR ǡĶ8d]c���9�ɩǯȕ¡´ǽ8ȌǶƜƦ7ř˘Mò?&�

ǰ7ģƬŬɊ8Ğú7��29�PT-INR �ƚ� PT-INR �tj��\8Ù

7ȌǶ&2�-öɔū��I�&-�02�Ŷ�9 WF 7FIʭÝ6žÐ

ĒäƱ8Ďʴ�F; PT-INR �ƚŞ8ǽʽʉƒ�ʱÔ3�I�Mʁº(I

-C7�µǽˁĮŞƢÕ8 1 �ƣ˂9ljʩ PT-INR M�tj��\(I#

4MƇĪ(=�4ɉ�I�

ʣō�ɢʱžÐĒȯǸ8ƕ&�ƃƽ4&2 Time in therapeutic range 8

ƺũ�ƈĉ%J�WF �ǏȋěÍ7_�q���%J-Ʀ˂�Òɬ4��

Ü´ǽ8�d[|O[j�4&2Ƥǽ6ƃƽ46I#4�ĝĂ%J2�I

47)�WF 4^|Qlt}�F;T��lt}µǽ�7��29 TTR �ǟŃ

&�PT-INR ǡĶĎƑ9Ġá(IÃÿ��I#4�ƛG�76H˥Table 12,

13 �˦2 ÛµǽƜ7�!I PT-INR _�q���8ˑ&%��I#4�ȜĈ

%J-�@-�^|Qlt} /T��lt}ªģ8 TKIs 7��2D 7 ·3

TKIs µǽŞ7 PT-INR _�q�����ɤ46IÃÿMʄC-�WF 8ž

ÐĒäƱ8ĠŖ7FH�PT-INR �ǏȋěMʙ�-Ʀ˂�Ġá&2�-#4

�˥µǽÙ˪7.3ˤ , µǽŞ˪30.1ˤ �˦TKIs 4 WF µǽŞ7 TTR �±�&

-�6ɳď3�I4ɉ�GJ-�

PT-INR �ƚ7˃�(I4ɉ�GJIŬɊďı79ōˣ˥ ˡˣ �˦ŤȆŬ�

ɋȆŬ�əȆŬ�±P�}��ɬȈ�Ƅ"GJI 51,52)�ɋȆŬ39ɋɟ3

Ǽǻ%JI{j�� K¹IJūɬǙÐĒďı8±�E WF8ɋ©ʍ±��ï

ď4&2ɉ�GJ�əȆŬ7��29 WF 8ɩǯåű<8ř˘9Ń6 �

ɬłƮǀɔ�Êȭ�GÒɬ�d[�Ġĥ(Iöɔū��I4ĝĂ%J2�

I 53,54)�±P�}��ɬȈ39ɬǥP�}��8±�7FH�ʬːŘ8

49

WF Ǩő��ƚ&�WF 8´ǽ�ĠŖ(Iöɔū��I48ĝĂ�6%J2

�I 55)�&�&�WF ³Íåű8ǰţ¨!9 CLpof ≈ CLintH, Cpsspof =

(D/τ)/CLpof = (D/τ)/CLintH 3�H�ʬːŘ8 WF Ǩő9 CLintH 7F02Ǎ

Ķ%JI�+8-C�ɬǥP�}��8±�7FI fuB 8�ƚ9 WF 8³

Íåű7>4N5ř˘&6�4ɉ�GJ�±P�}��ɬȈƜ8 PT-INR

�ƚ79+8§8ɳď�˃�&2�Iöɔū�ɉ�GJI�&�&�Ŷ�

8șȨ_��q39əǀɔEɋǀɔ7Ƥů6Ģæ9ʄCGJ6�0-�

WF 9ɋɟ7��2{j�� K 4Ƃž&�{j�� K T�YbrʵÆ

ʹȹMȪúȏ7˅Ĺ(I-C�ɬǙÐĒďı3�IȬ ����� ďı

8ǻŵ�˅Ĺ%JžÐĒäƱMȜ(�WF ɰÛ9 S ³4 R ³8Èijȅū³

�G6I�f�³ǜúǯ3�I��+8žÐĒǕū9 S-WF 8Ɩ� R-WF

FHD 3-5 ¿ˡ 56)�S-WF 9�7 CYP2C9�R-WF 9 CYP1A1�CYP1A2�

CYP2C19�CYP3A4 65Ȧ�8©ʍʹȹ7FHǘĨ(I#4�ĝĂ%J2

�I 57)�&-�02�žÐĒäƱ7ř˘(I³Íåű�8Ģåɳď9ʬː

Ř S-WF 8ɋ©ʍǕū�(6L/ CYP2C9 Ǖū3�I4ɉ�GJI�+8

-C TKIs 4 WF 8ɩǯ˂ȕ¡´ǽ�Wte�79 CYP2C9 Ǖū˅Ĺ�Ŗ

˃�&2�Iöɔū��H�¥Ş CYP2C9 M¦&-ȕ¡´ǽ�Wte�

71�2ƛG�7(I#4�ʻɳ3�I��Ɩ3�R-WF Ǩő��ƚ&-

Ğú7��29�~�q��{�Ɯ˂ò; PT-INR 7Ŀ(IƤů6ř˘9

ʄCGJ6�0-48ĝĂ��H 58)�R-WF 8©ʍʹȹ3�I CYP1A1�

CYP1A2�CYP2C19�CYP3A4 Ǖū˅Ĺ8˃�9±�4ɉ�I�

� ƩșȨ3Ŀʏ460- 9 Ȧ8 TKIs 8�/�P|Olt}9³Í�G8

ǘĨ7Ŀ(Ibq[�� P450 8˃�9±���+8§8 TKIs 9�7^|

Qlt} C˪YP3A4/2D6�T��lt} C˪YP3A4� P�[lt} C˪YP3A4�

50

PYblt}˪ CYP3A4/5�[�ilt}˪ CYP3A4/5�yiyt}˪ CYP3A4�

�`�|St}˪CYP3A4 ò;\�[��ʺʜȣʹȹ˥UGT˦1A9�x�

pjt}˪CYP3A4 3©ʍ%JI#4�ĝĂ%J2�H 59,60)�ù©ʍʹȹ

MʅŁ�˅Ĺ(IɩÛ48µǽ9Ǔů�ťɳ3�I�

� Ŷ�9zqɋ�[�i��7FI in vitroȷ8 S-WF8©ʍ˅Ĺķˠ7F

H�^|Qlt}ET��lt}� CYP2C9 ˅ĹǕūMƤ(I#4MĝĂ

&- 43)�Table 15 79�^|Qlt} /T��lt}8˔IJĖ��F;IJĖ

�38 in vitro CYP2C9 Ǖū71�2@4C-�100 µM 3^|Qlt}�

F;T��lt}9�+J,J (S)-WF-7-OH 8 67ˤ�F; 46ˤ8˅ĹMȜ

&-�^|Qlt}4T��lt}8ŌęĶŋDZűɬ�Ǩő9�1 ƙ 1 Ď

250 mg 8^|Qlt}@-9 150 mg 8T��lt}Mƥǽ&2�IŬɊ

7��2�+J,J 0.59 µM �F; 5.6 µM 3�I4ʭð8Ɠdz3ĝĂ%J

2�I� 61,62)�in vitroȷ7��2Ōę 1 µM8^|Qlt}� (S)-WF-7-OH

M 36ˤ˅Ĺ�10 µM 8T��lt}� (S)-WF-7-OH M 27ˤ˅Ĺ(I#4M

Ȝ&-�#JG�G�^|Qlt}�F;T��lt}4 WF 8ȕ¡´ǽ

79 CYP2C9 ©ʍ˅Ĺ��ʸ˃�&2�Iöɔū�ɉ�GJ-�

� üƼ8ķˠ7FH^|Qlt}�T��lt}ªģ8 7 Ȧ8 TKIs˥10

�M˦IJĖ�3 CYP2C9 ©ʍǕūMǡĶ&-4#K�P�[lt}Ex�

pjt}39˅ĹǕū9Ȝ%6�0-��+Jªģ8 5 Û39�)JD

30ˤª�8˅ĹǕū�ʄCGJ�ǰ7�`�|St}9 80ˤª�8©ʍ˅

ĹMȜ&-˥Table 16, Fig. 15˦�P�[lt}�x�pjt}ªģ8 5 Û

7˃&29ȕ¡´ǽ7 CYP2C9 ©ʍ˅Ĺ��ʸ˃�&2�Iöɔū�ɉ�

GJI�¥Ď8ʉƲȾƱ39�˅ĹǕūMȜ%6�0-P�[lt}�x

�pjt}DĀC��)J8 TKIs 3DĿʏŬɊ7 PT-INR �ƚ�ʄCGJ

51

2�H�CYP2C9 M¦&-ɩǯåű�8ȕ¡´ǽ8§7D�ɩßij�8ȕ

¡´ǽ�IJĖ(Iöɔū��I4ɉ�GJI�WF 9ɋɟ7��2�{j

�� K 4Ƃž&2{j�� K T�YbrʵÆʹȹ˥VKORC1˦M˅Ĺ(I

#47FH�{j�� K ¹IJūɬǙÐĒďı3�IȬ ����� ď

ı8ǻŵ�˅Ĺ%JžÐĒäƱMȜ( 57)�Ƚõž�Nɩ3�IW�bj{

�39 3 [��˥1 [��˪14 ƙ˂ƥǽ 7 ƙ˂«ɩ˦Ž�7FH�ÐĒȬ

ďıǕū�±�&-48ĝĂ��I 63)�TKIs 7��2D WF 4üƼ7Ð

ĒďıǕūM±�(Iöɔū��I�¥Ş9 VKORC1 M¦&- WF 4 TKIs

8ȕ¡´ǽ8ƤǬ71�2ƛG�7(I#4�ʻɳ3�I�@-�¥Ď8

ķˠȾƱ9 TKIs � CYP2C9 M¦&-˅ĹMɭ��71�2Țʄ&-d[

��t�\ķˠ3�I� In vitro �G in vivo <8©ʍ˅Ĺ8�ǡMɭ�-

C79ɋɟ�38˅Ĺɩ8ʬːŘǨő4˅ĹĶƑ˥ki˦�ťɳ4ɉ�I�

Table 15� ^|Qlt}�F;T��lt}7�!I S-��|O��©ʍ

˅ĹǴ

Data are mean values ± SD of triplicate experiments.

Abbreviation: V, velocity of (S)-warfarin 7-hydroxylation reaction.

Inhibitor Concentration (µM) V (pmol/nmol P450/min) Inhibition %

0 µM 2.81 ± 0.08 0

Gefitinib 1 µM 1.79 ± 0.36 36.4 ±13.0

Gefitinib 10 µM 1.64 ± 0.02 41.6 ± 0.9

Gefitinib 100 µM 0.94 ± 0.08 66.6 ± 3.0

Erlotinib 1 µM 2.81 ± 0.13 -0.1 ± 4.5

Erlotinib 10 µM 2.05 ± 0.17 27.0 ± 6.2

Erlotinib 100 µM 1.52 ± 0.11 45.9 ± 3.7

52

Table 16� 7 Ȧ8l�b�Ys�g˅Ĺɩ7�!I S-��|O��©ʍ˅

ĹǴ

S-warfarin concentration was used 2 µMa or 4 µMb, respectively

Data are mean values ± SD of triplicate experiments.�

Fig. 15� 9 Ȧ8l�b�Ys�g˅Ĺɩ˥10 µM˦7FI S-��|O��©

ʍ˅ĹǴ8NJʝ

Inhibitor (10 µM) Inhibition (%)

Afatiniba 37.4 ± 13.5

Alectiniba -19.2 ± 3.9

Axitiniba 29.8 ± 7.3

Crizotinibb 48.0 ± 8.7

Pazopanibb 37.5 ± 8.3

Regorafenibb 87.1 ± 3.1

Vandetaniba -19.6 ± 7.5

y�4]ÊÉË�

"TKIs£ CYP2C9�4W> ¨.��a¥­

"TKIs£¨��®«PT-INR�H�v[�@ÊPK˧�¦� v�2�ÊPD˧g��_�1'�­ u>

l2m��Êp5Ë

0.0

20.0

40.0

60.0

80.0

100.0

Alectinib Vandetanib Erlotinib Axitinib Afatinib Pazopanib Gefitinib Crizotinib Regorafenib

53

Ŷ�8șȨ79� 1�8ˇȃ��I�Ȭ�7�ƩșȨ3Ŷ��ʉƲ&

-ŬɊƑ9˔ŋ7ˇGJ2�H�TTR 7Ŀ(Iɩǯȕ¡´ǽ8ř˘MèÓ

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7ĥ� Ļ�(Iöɔū��IŬɊ8ɩǸʳ­ijȏŮĝMŠI#4�3�

6�0-�PT-INR Ģå9 TKIs MŽ�%JI�NȦEʳ­ȏɐƝ7¹IJ&

2�Iöɔū��H�WF-TKIs ȕ¡´ǽ3ɷĽ%J-¾¤˂8ʮ�Mʇƛ

(I-C79ŬɊ8ɩǸʳ­ijȏŮĝMĀC-ř˘ďıMʁº(IĤĢʽ

ɸƯșȨ65�¥Şťɳ4ɉ�I�

� WF 4 TKIs 9+J,J§ȢE§ˈ3ÑƖ%JI#4DĤ �WF 4 TKIs

8ȕ¡´ǽ9ɠŏǶĞ39ɴʧ%JIöɔū��I�%G7�Ĥ 8�N

æijȋǑ9ǶĖ�ģƬ3ˁĮ%J2�I�ƩƸɻ7�!IȾƱ9�WF 4

^|Qlt} /T��lt}µǽˁĮŞ8ƢÕ8 1 �ƣ˂9ljʩ8 PT-INR

�tj��\� WF 7FIʭÝ6žÐĒäƱĠŖMĎʴ(I87Ƥǽ3�

I#4MȜĈ&2�I�Ơ7�ǏȋěȱđÍ3 PT-INR � 2 Ďʨɀ&2Ġ

á&-Ğú�ǰ7ģƬ3ǏȋMô!2�IŬɊ39žÐĒǕū�ʭÝ76

02&@�öɔū��H�WF Ž�ʽ8ʉƒMɉų(Iťɳ��I4ɉ�

GJ-�@-�¥Ď8ʉƲ7FH WF 8ǝ¨Ɠơ7ȕ¡´ǽ7˃(Iɼʞ

86� 7 Ȧ8 TKIs 7��2D�WF 48µǽ3 PT-INR �ƚMʄC-�ª

�8Ƹɻ�G WF 4 TKIs 48ȕ¡´ǽ9Ȥ396 �µǽ(I4 PT-INR

�ǏȋěMʫɗ&�Òɬ�d[�ˡ@Iöɔū�ȜĈ%J-�

54

łƁ

� ^|Qlt} /T��lt}7�!I PT-INR �ƚ8ȌǶƜƦ�ħÀ9 7

ƙ /9 ƙ3�0-��µǽˁĮŞ 1-4 ʩȓ@39ùʩ3 PT-INR �ƚ�ʄC

GJ2�H�µǽˁĮŞ 1 �ƣ˂9ljʩ�PT-INR �tj��\Mɭ�ťɳ

��I4ɉ�GJI�@-�ʦˈÙ7ǏȋěÍ3ʨɀ&- PT-INR �ƚM

ʄC�ģƬ<ȣɭ&2�GǏȋěMʙ�- PT-INR �ƚ�ȌǶ&-Ȉ·D

ʄCGJ�PT-INR �ǏȋěÍ3�02D PT-INR �ƚ�ʨɀ&-Ğú79

WF Ž�ʽ8ʉƒMɉų(Iťɳ��I4ɉ�GJ-�ƩșȨ39^|Q

lt} /T��lt}ªģ8 7 Ȧ8 TKIs 3D PT-INR �ƚ�ʄCGJ-�

ǝ¨Ɠơ7ȕ¡´ǽ8ɼʞ86� TKIs3DWF48ȕ¡´ǽ�IJĖ(Iö

ɔū�ȜĈ%J-�

55

ƩșȨ8ɁƁ

� ƩșȨ7FH�Ɏ�NŬɊ7��2PcPʋē39±�4%J2�-

VTE ȌȈ˜ő�ǂȴʋē4Ʃʶ3üȭ3�I#4MȜ(#4�3�-�@

-�ǂȴ3ǽ�GJ2�I KRS/VRS 9ƙƩ¤Ɏ�NŬɊ8 VTE ȌȈ�d

[ʁº7ǽ�I#49ʱÔ396 �Ʃʶ8Ɏ�NŬɊ7��29 BMI

25 kg/m2�ȎɬǷƑ˭11�109/L�D-dimer 1.44 µg/mL�˔łȺɑɎ�N8

4 18 VTE ȌȈ�d[ďı�ƀÒ%J-�%G79�ƙƩ¤�NŬɊ7�

�2 BMI 25 kg/m2ª�3�I#4� VTE ȌȈ�d[ďı46I#4�Õ

C2ƛG�460-�@-�Òɬ�d[8ˡ�ȇű3�I�NŬɊ7��

2�žÐĒȋǑ7¶ǽ%JI WF 4�NǏȋ7ǽ�GJI TKIs 8µǽ7F

Iȕ¡´ǽ9Ȥ396 �ǝ¨Ɠơ7�!Iȕ¡´ǽŮĝ8ƤǬ7˃LG

)�¥ĎĿʏ460-(=28 TKIs 8µǽ3 WF 8žÐĒäƱ8ĠŖ�ʘ

#02&@�-C��Ɋ8µǽƜ79 WF 8ǟʽ�ťɳ3�I4��ʻɳ

6ȕ¡´ǽŮĝMɠŏǶĞ<ƈ¸(I#4�3�-�ƩșȨ7FH�Nɿ

ȋ7�!I VTE Ǐȋ8�vc��q7ʑdz3�-4ɉ�I�

56

ʍʡ

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@(�

� @-ÜƲ4&2ʒʻ6$ůɴ�$ƃŁMʔH@&-ƛǏɩȢĥijɩijʸ

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57

ñɉƓdz

1) Lyman G.H., Khorana A.A., Falanga A., Clarke-Pearson D., Flowers C.,

Jahanzeb M., Kakkar A., Kuderer N.M., Levine M.N., Liebman H.,

Mendeison D., Raskob G., Somerfield M.R., Thodiyil P., Trent D., Francis

C.W.; American Society of Clinical Oncology, J. Clin. Oncol., 25,

5490-5505 (2007).

2) Khorana A.A., Francis C.W., Culakova E., Kuderer N.M., Lyman G.H., J.

Thromb. Haemost., 5, 632-634 (2007).

3) Varki A., Blood, 110, 1723-1729 (2007).

4) Horsted F., West J., Grainge M.J., PLoS. Med., 9, e1001275 (2012).

5) Heit J.A., Silverstein M.D., Mohr D.N., Petterson T.M., O'Fallon W.M.,

Melton L.J. 3rd, Arch. Intern. Med., 160, 809-815 (2000).

6) Prandoni P., Lensing A.W., Piccioli A., Bernardi E., Simioni P., Girolami B.,

Marchiori A., Sabbion P., Prins M.H., Noventa F., Girolami A., Blood, 100,

3484-3488 (2002).

7) ưʢŔ , ʾƧĵǏ , ����� , 46, 621-628 (2008).

8) Andreasen P.A., Kjøller L., Christensen L., Duffy M.J., Int. J. Cancer, 72,

1-22 (1997).

9) Chen H.X., Cleck J.N., Nat. Rev. Clin. Oncol., 6, 465-477 (2009).

10) Khorana A.A., Kuderer N.M., Culakova E., Lyman G.H., Francis C.W.,

Blood, 111, 4902-4907 (2008).

11) Ay C., Dunkler D., Marosi C., Chiriac A.L., Vormittag R., Simanek R.,

Quehenberger P., Zielinski C., Pabinger I., Blood, 116, 5377-5382 (2010).

12) Khorana A.A., Francis C.W., Culakova E., Lyman G.H., Cancer, 104,

58

2822-2829 (2005).

13) Khorana A.A., Connolly G.C., J. Clin. Oncol., 27, 4839-4847 (2009).

14) Ay C., Vormittag R., Dunkler D., Simanek R., Chiriac A.L., Drach J.,

Quehenberger P., Wagner O., Zielinsky C., Pabinger I., J. Clin. Oncol., 27,

4124-4129 (2009).

15) Pabinger I., Thaler J., Ay C., Blood, 122, 2011-2018 (2013).

16) Kearon C., Akl E.A., Ornelas J., Blaivas A., Jimenez D., Bounameaux H.,

Huisman M., King C.S., Morris T.A., Sood N., Stevens S.M., Vintch JR.E.,

Wells P., Woller S.C., Moores L., Chest, 149, 315-352 (2016).

17) Holbrook A.M., Pereira J.A., Labiris R., McDonald H., Douketis J.D.,

Crowther M., Wells P.S., Arch. Intern. Med., 165, 1095-1106 (2005).

18) Greenblatt D.J., von Moltke L.L., J. Clin. Pharmacol., 45, 127-132 (2005).

19) Hata T., Kudo T., Sakai D., Takahashi H., Haraguchi N., Nishimura J., Hata

T., Mizushima T., Yamamoto H., Doki Y., Mori M., Satoh T., Cancer

Chemother. Pharmacol., 78, 389-396 (2016).

20) Sánchez G.E., Arco P.Y., Farm. Hosp., 38, 338-363 (2014).

21) Hiraide M., Shiga T., Minowa Y., Nakano Y., Yoshioka H., Suzuki K.,

Yasuda C., Takahashi H., Hama T., J. Cardiol., (accepted on June 27, 2019).

22) Zhang Y., Yang Y., Chen W., Guo L., Liang L., Zhai Z., Wang C., Chest,

146, 650-658 (2014).

23) Japan Society for the Study of Obesity, editors. Guidelines for the

management of obesity disease 2016, Tokyo: Life science; 2016.

24) ƪʼė÷ , țʸą˚ , ɦĘȔ , ƫƭˋı , ²ʼÚ , ˡ¢ˏ ʷ , Ʃ˂Ƴ ,

� , 49, 151-156 (2009).

59

25) Kato H., Kashiwagi H., Shiraga M., Tadokoro S., Kamae T., Ujiie H., Honda

S., Miyata S., Ijiri Y., Yamamoto J., Maeda N., Funahashi T., Kurata Y.,

Shimomura I., Tomiyama Y., Kanakura Y., Arterioscler. Thromb. Vasc.

Biol., 26, 224-230 (2006).

26) Ay C., Pabinger I., Cohen A.T., Thromb. Haemost., 117, 219-230 (2017).

27) Vitale C., D'Amato M., Calabrò P., Stanziola A.A., Mormile M., Molino A.,

Multidiscip. Respir. Med., 10, 28 (2015).

28) Blom J.W., Osanto S., Rosendaal F.R., J. Thromb. Haemost., 2, 1760-1765

(2004).

29) Labelle M., Hynes R.O., Cancer Discov., 2, 1091-1099 (2012).

30) Gu B., Gao W., Chu H., Gao J., Fu Zhi., Ding H., Lv J., Wu Q., Medicine,

95, e3752 (2016).

31) ŌÒʆ , ɨʟˏ� , �ʼǔļ , ûŇȠć , ʾƧʕ� , ŦʓĦʷ , ˡƿƞ

Ɇ , ǩƎœ , ������ , (accepted on February 13, 2019).

32) Carrier M., Abou-Nassar K., Mallick R., Tagalakis V., Shivakumar S.,

Schattner A., Kuruvilla P., Hill D., Spadafora S., Marquis K., Trinkaus M.,

Tomiak A., Lee AYY., Gross P.L., Lazo-Langner A., El-Maraghi R., Goss

G., Le Gal G., Stewart D., Ramsay T., Rodger M., Witham D., Wells P.S.,

AVERT Investigators, N. Engl. J. Med., 380, 711-719 (2019).

33) Khorana A.A., Soff G.A., Kakkar A.K., Vadhan-Raj S., Riess H., Wun T.,

Streiff M.B., Garcia D.A., Liebman H.A., Belani C.P., O'Reilly E.M., Patel

J.N., Yimer H.A., Wildgoose P., Burton P., Vijapurkar U., Kaul S.,

Eikelboom J., McBane R., Bauer K.A., Kuderer N.M., Lyman G.H.,

CASSINI Investigators, N. Engl. J. Med., 380, 720-728 (2019).

60

34) Kohno T., Ichikawa H., Totoki Y., Yasuda K., Hiramoto M., Nammo T.,

Sakamoto H., Tsuta K., Furuta K., Shimada Y., Iwakawa R., Ogiwara H.,

Oike T., Enari M., Schetter A.J., Okayama H., Haugen A., Skaug V., Chiku

S., Yamanaka I., Arai Y., Watanabe S., Sekine I., Ogawa S., Harris C.C.,

Tsuda H., Yoshida T., Yokota J., Shibata T., Nat. Med., 18, 375-377 (2012).

35) Arai S., Mitsufuji H., Nishii Y., Onoda S., Ryuge S., Wada M., Katono K.,

Iwasaki M., Takakura A., Otani S., Yamamoto M., Yanaihara T., Yokoba M.,

Kubota M., Katagiri M., Fukui T., Kobayashi H., Yanase N., Hataishi R.,

Masuda N., Int. J. Clin. Oncol., 14, 332–336 (2009).

36) Thomas K.S., Billingsley A., Amarshi N., Nair B.A., Am. J. Health-syst.

Pharm., 67, 1426–1429 (2010).

37) ��|O��®ʿ ǝ¨Ɠơ , Ȭ 27 Ǯ , 2019.

38) Kubomura Y., Ise Y., Wako T., Katayama S., Noro R., Kubota K., J. Nippon

Med. Sch., 84, 291-293 (2017).

39) Kitade H., Hiromasa-Yamasaki A., Hokkoku K., Mori M., Watanabe M.,

Nakai M., Yano S., J. Pharm. Health. Care. Sci., 2, 15 (2016).

40) Shiozawa K., Watanabe M., Hirano N., Wakui N., Kikuchi Y., Hara F., Ishii

K., Iida K., Sumino Y., Gan To Kagaku Ryoho, 38, 1713-1715 (2011).

41) Chintakuntlawar A.V., Finnes H.D., Tefferi A., Pardanani A., Leukemia &

Lymphoma, 55, 2213-2214 (2014).

42) Breccia M., Santopietro M., Loglisci G., Stagno F., Cannella L., Carmosino

I., Alimena G., Leuk. Res., 34, e224-e225 (2010).

43) Hiraide M., Minowa Y., Nakano Y., Suzuki K., Shiga T., Nishio M.,

61

Miyoshi J., Takahashi H., Hama T., J. Oncol. Pharm. Pract., in press. doi:

10.1177/1078155218801061.

44) ŌÒʆ , ɨʟˏ� , �ʼǔļ , ʾƧʕ� , ŦʓĦʷ , �ĬǛ� , ˡƿƞ

Ɇ , ǩƎœ , ������ , (accepted on April 5, 2019).

45) Verhovsek M., Moffat K.A., Hayward C.P., Am. J. Hematol., 83, 928-931

(2008).

46) Magagnoli M., Masci G., Castagna L., Morenghi E., Santoro A., Ann. Oncol.,

17, 174-176 (2006).

47) Rosendaal F.R., Cannegieter S.C., van der Meer F.J., Briet E., Thromb.

Haemost., 69, 236-239 (1993).

48) Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary

Thromboembolism and Deep Vein Thrombosis (JCS2017), Available at:

http://www.j-circ.or.jp/guideline/pdf/JCS2017_andoh_h.pdf. accessed 23

December, 2017.

49) Japanese Circulation Society. Guidelines for pharmacotherapy of atrial

fibrillation (JCS2013), Available at:

http://www.jcirc.or.jp/guideline/pdf/JCS2013_inoue_h.pdf. accessed 10

December, 2016.

50) The Japan Stroke Society. Japanese guidelines for the management of stroke

2015, Available at: http://www.jsts.gr.jp/jss08.html accessed 10 December,

2016.

51) Abdelhafiz A.H., Myint M.P., Tayek J.A., Wheeldon N.M., Clin. Ther., 31,

1534–1539 (2009).

62

52) Dimarco J.P., Flaker G., Waldo A.L., Corley S.D., Greene H.L., Safford

R.E., Rosenfeld L.E., Mitrani G., Nemeth M., AFFIRM Investigators, Am.

Heart. J., 149, 650–656 (2005).

53) Gawaz M.P., Dobos G., Späth M., Schollmeyer P., Gurland H.J., Mujais

S.K., J. Am. Soc. Nephrol., 5, 36-46 (1994).

54) Escolar G., Cases A., Bastida E., Garrido M., López J., Revert L., Castillo

R., Ordinas A., Blood, 76, 1336-1340 (1990).

55) Mullokandov E., Ahn J., Szalkiewicz A., Babayeva M.,Austin., J.

Pharmacol. Ther., 2, 3, (2014).

56) Kaminsky L.S., Zhang Z.Y., Pharmacol. Ther., 73, 67-74 (1997).

57) Weitz J.I., Blood coagulation and anticoagulant, fibrinolytic and antiplatelet

drugs. In: Brunton L.L., Chabner B. and Knollman B. (eds) Goodman &

Gilman’s The pharmacological basis of therapeutics, 12th ed. New York:

McGraw-Hill, 2011.

58) Shen Z., Lee C.A., Wallach K., Valdez S., Wilson D.M., Kerr B., Gillen M.,

Clin. Pharmacol. Drug. Dev., 8, 657-663 (2019).

59) Duckett D.R., Cameron M.D., Expert. Opin. Drug. Mtab. Toxicol., 6,

1175-1193 (2010).

60) Teo Y.L., Ho H.K., Chan A., Br. J. Clin. Phramcol., 79, 241-253 (2015).

61) Nakamura Y., Sotozono C., Kinoshita S., Exp. Eye. Res., 72, 511-517

(2001).

62) Yamamoto N., Horiike A., Fujisaka Y., Murakami H., Shimoyama T.,

63

Yamada Y., Tamura T., Cancer Chemother. Pharmacol., 61, 489-496

(2008).

63) Camidge R., Reigner B., Cassidy J., Grange S., Abt M., Weldekamm E.,

Jodrell D., J. Clin. Oncol., 23, 4719-4725 (2005).

64

Appendix 1. List of 59 concomitant drugs known to interact with warfarin

and TKIs, affect the PT-INR and induce bleeding complications.

Therapeutic Classification Drugs

Anticonvulsants

Phenobarbital1)

Carbamazepine2,3)

Phenytoin4)

Sodium valproate5)

Antiarrhythmics Amiodarone6-8)

Serotonin reuptake inhibitors

Paroxetine hydrochloride

hydrate9)

Sertraline hydrochloride10)

Fluvoxamine maleate11,12)

Serotonin and norepinephrine

reuptake inhibitors Duloxetine13)

Tricyclic antidepressants

Amitriptyline hydrochloride14)

Nortriptyline hydrochloride14)

Statins

Simvastatin15,16)

Fluvastatin sodium17)

Rosuvastatin Calciuma,18)

Fibrates

Bezafibrate19)

Clofibrate20)

Fenofibrate21)

65

Proton pump inhibitors

Omeprazole22-25)

Lansoprazolea,25)

Esomeprazolea, 25,26)

H2 antagonists

Cimetidine27-32)

Ranitidine27,28,33)

Famotidinea,34)

Platelet aggregation inhibitors

Aspirina,35,36)

Ethyl icosapentate37,38)

Ozagrel sodium37)

Clopidogrel36)

Cilostazola,39)

Ticlopidine hydrochloride40)

Beraprost sodium37)

Limaprost alfadex38,41)

Vitamin K2 Menatetrenone42)

Anti-gout Preparations Benzbromarone43)

Allopurinola,44)

Sulfonylurea Antidiabetics

Glibenclamide45)

Glimepiride45)

Chlorpropamide45)

Tolbutamide45)

Rifamycin Antibiotics Rifampicin46-49)

66

Macrolide Antibiotics

Erythromycin50)

Clarithromycin51)

Azithromycin52)

Fluoroquinolone Antibiotics

Ofloxacin53,54)

Ciprofloxacin55,56)

Levofloxacin57)

Sulfonamide and Trimethoprim

Antibiotic Sulfamethoxazole/trimethoprim58)

Antitrichomonals Metronidazole59)

Azole Antifungals

Itraconazole60)

Fluconazole61,62)

Voriconazole63)

Miconazole64)

Analgesics with/without Antipyretic

Activity Acetaminophena,65)

Nonsteroidal Antiinflammatory Drugs

Bucolome66-69)

Ibuprofen70)

Indomethacin71)

Diclofenac72)

Loxoprofena,73-75)

Celecoxib76,77)

Opioid Agonists Tramadol hydrochloridea,78,79)

aDrugs used with warfarin in the present study.

67

Reference

1) Orme M., Breckenridge A., N. Engl. J. Med., 295, 1482-1483 (1976).

2) Hansen J.M., Siersboek-Nielsen K., Skovsted L., Clin. Pharmacol. Ther., 12,

539-543 (1971).

3) Clark N.P., Hoang K., Delate T., Horn J.R., Witt D.M., Clin. Appl. Thromb.

Hemost., 24, 172-178 (2018).

4) Levine M., Sheppard I., Clin. Pharm., 3, 200-203 (1984).

5) Yoon H.W., Giraldo E.A., Wijdicks E.F., Neurocrit. Care., 15, 182-185

(2011).

6) Heimark L.D., Wienkers L., Kunze K., Gibaldi M., Eddy A.C., Trager W.F.,

O'Reilly R.A., Goulart D.A., Clin. Pharmacol. Ther., 51, 398-407 (1992).

7) Almog S., Shafran N., Halkin H., Weiss P., Farfel Z., Martinowitz U., Bank

H., Eur. J. Clin. Pharmacol., 28, 257-261 (1985).

8) O’Reilly R.A., Trager W.F., Rettie A.E., Goulart D.A., Clin. Pharmacol.

Ther., 42, 290-294 (1987).

9) Bannister S.J., Houser V.P., Hulse J.D., Kisicki J.C., Rasmussen J.G., Acta.

Psychiatr. Scand. Suppl., 350, 102-106 (1989).

10) Apseloff G., Wilner K.D., Gerber N., Tremaine L.M., Clin. Pharmacokinet.,

32, 37-42 (1997).

11) Yap K.B., Low S.T., Singapore Med. J., 40, 480-482 (1999).

12) Limke K.K., Shelton A.R., Elliott E.S., Ann. Pharmacother., 36, 1890-1892

(2002).

13) Glueck C.J., Khalil Q., Winiarska M., Wang P., JAMA, 295, 1517-1518

(2006).

68

14) Pond S.M., Graham G.G., Birkett D.J., Wade D.N., Clin. Pharmacol. Ther.,

18, 191-199 (1975).

15) Gaw A., Wosornu D., Lancet, 340, 979-980 (1992).

16) Lin J.C., Ito M.K., Stolley S.N., Morreale A.P., Marcus D.B., J. Clin.

Pharmacol., 39, 86-90 (1999).

17) Trilli L.E., Kelley C.L., Aspinall S.L., Kroner B.A., Ann. Pharmacother., 30,

1399-1402 (1996).

18) Simonson S.G., Martin P.D., Mitchell P.D., Lasseter K., Gibson G., Schneck

D.W., J. Clin. Pharmacol., 45, 927-934 (2005).

19) Beringer T.R., Postgrad. Med. J., 73, 657-658 (1997).

20) O’Reilly R.A., Sahud M.A., Robinson A.J., Thromb. Diath. Haemorrh., 27,

309-318 (1972).

21) Ascah K.J., Rock G.A., Wells P.S., Ann. Pharmacother., 32, 765-768

(1998).

22) Sutfin T., Balmer K., Bostrom H., Eriksson S., Höglund P., Paulsen O., Ther.

Drug. Monit., 11, 176-184 (1989).

23) Unge P., Svedberg L.E., Nordgren A., Blom H., Andersson T., Lagerström

P.O., Idström J.P., Br. J. Clin. Pharmacol., 34, 509-512 (1992).

24) Uno T., Sugimoto K., Sugawara K., Tateishi T., Ther. Drug. Monit., 30,

276–281 (2008).

25) van Leeuwen R.W., Jansman F.G., Hunfeld N.G., Peric R., Reyners AKL.,

Imholz ALT., Brouwers JRBJ., Aerts J.G., van Gelder T., Mathijssen RHJ.,

Clin. Pharmacokinet., 56, 683-688 (2017).

26) Andersson T., Hassan-Alin M., Hasselgren G., Rohss K., Clin.

69

Pharmacokinet., 40, 523-537 (2001).

27) Toon S., Hopkins K.J., Garstang F.M., Rowland M., Eur. J. Clin.

Pharmacol., 32, 165-172 (1987).

28) O’Reilly R.A., Arch. Intern. Med., 144, 989-991 (1984).

29) Bell W.R., Anderson K.C., Noe D.A., Silver B.A., Arch. Intern. Med., 146,

2325-2328 (1986).

30) Serlin M.J., Sibeon R.G., Mossman S., Breckenridge A.M., Williams J.R.,

Atwood J.L., Willoughby J.M., Lancet, 2, 317-319 (1979).

31) Sax M.J., Randolph W.C., Peace K.E., Chretien S., Frank W.O., Braverman

A.J., Gray D.R., McCree L.C., Wyle F., Jackson B.J., Clin. Pharm., 6,

492-495 (1987).

32) Hunt B.A., Sax M.J., Chretien S., Pharmacotherapy, 9, 184 (1989).

33) Baciewicz A.M., Morgan P.J., Ann. Intern. Med., 112, 76-77 (1990).

34) Karlstadt R.G., Arch. Intern. Med., 151, 810, 814, 815 (1991).

35) O'Reilly R.A., Sahud M.A., Aggeler P.M., Ann. N.Y. Acad. Sci., 179,

173-186 (1971).

36) Shireman T.I., Howard P.A., Kresowik T.F., Ellerbeck E.F., Stroke, 35,

2362-2367 (2004).

37) Hansen P.W., Clemmensen L., Sehested T.S., Circ. Cardiovasc. Qual.

Outcomes., 9, 621-628 (2016).

38) Tamura T., Sakaeda T., Kadoyama K., Okuno Y., Int. J. Med. Sci., 9,

441-446 (2012).

39) Mallikaarjun S., Bramer S.L., Clin. Pharmacokinet., 37 (suppl 2), 79-86

(1999).

70

40) Gidal B.E., Sorkness C.A., McGill K.A., Larson R., Levine R.R., Ther.

Drug. Monit., 17, 33-38 (1995).

41) Park T.K., Shin S.J., Lee J.H., Clin. Spine. Surg., 30, E104-E110 (2017).

42) Hara K., Akiyama Y., Tomiuga T., Kobayashi M., Kawashima H., Nihon.

Yakurigaku. Zasshi., 113, 185-192 (1999).

43) Takahashi H., Sato T., Shimoyama Y., Shioda N., Shimizu T., Kubo S.,

Tamura N., Tainaka H., Yasumori T., Echizen H., Clin. Pharmacol. Ther.,

66, 569-581 (1999).

44) Barry M., Feely J., Clin. Pharmacokinet., 19, 167-169 (1990).

45) Wilke R.A., Berg R.L., Vidaillet H.J., Caldwell M.D., Burmester J.K.,

Hillman M.A., Clin. Med. Res., 3, 207-213 (2005).

46) Almog S., Martinowitz U., Halkin H., Bank H.Z., Farfel Z., South. Med. J.,

81, 1304-1306 (1988).

47) Heimark L.D., Gibaldi M., Trager W.F., O'Reilly R.A., Goulart D.A., Clin.

Pharmacol. Ther., 42, 388-394 (1987).

48) O'Reilly R.A., Ann. Intern. Med., 83, 506-508 (1975).

49) Kusawake T., den Adel M., Groenendaal-van de Meent D., Adv. Ther., 34,

2466-2480 (2017).

50) Weibert R.T., Lorentz S.M., Townsend R.J., Cook C.E., Klauber M.R.,

Jagger P.I., Clin. Pharm., 8, 210-214 (1989).

51) Byers M., Can. J. Hosp. Pharm., 50, 285-287 (1997).

52) Foster D.R., Milan N.L., Pharmacotherapy, 19, 902-908 (1999).

53) Leor J., Matetzki S., Ann. Intern. Med., 109, 761 (1988).

54) Baciewicz A.M., Ashar B.H., Locke T.W., Ann. Intern. Med., 119, 1223

71

(1993).

55) Byrd D.C., Gaskins S.E., Parrish A.M., Freeman L.B., J. Am. Board. Fam.

Pract., 12, 486-488 (1999).

56) Israel D.S., Stotka J., Rock W., Sintek C.D., Kamada A.K., Klein C., Swaim

W.R., Pluhar R.E., Toscano J.P., Lettieri J.T., Heller A.H., Polk R.E., Clin.

Infect. Dis., 22, 251-256 (1996).

57) Ravnan S.L., Locke C., Pharmacotherapy, 21, 884-885 (2001).

58) O’Reilly R.A., Motley C.H., Ann. Intern. Med., 91, 34-36 (1979).

59) O'Reilly R.A., N. Engl. J. Med., 295, 354-357 (1976).

60) Yeh J., Soo S.C., Summerton C., Richardson C., BMJ., 301, 669 (1990).

61) Baciewicz A.M., Menke J.J., Bokar J.A., Baud E.B., Ann. Pharmacother. 28,

1111 (1994).

62) Black D., Evans J., Seaton T., Clin. Pharmacol. Ther., 51, 52 (1992).

63) Purkins L., Wood N., Kleinermans D., Nichols D., Br. J. Clin. Pharmacol.,

56, 24-29 (2003).

64) O’Reilly R.A., Goulart D.A., Kunze K.L., Neal J., Gibaldi M., Eddy A.C.,

Trager W.F., Clin. Pharmacol. Ther., 51, 656-667 (1992).

65) Gebauer M.G., Nyfort-Handsen K., Henschke P.J., Gallus A.S.,

Pharmacotherapy, 23, 109-112 (2003).

66) Takahashi H., Kashima T., Kimura S., Murata N., Takaba T., Iwade K., Abe

T., Tainaka H., Yasumori T., Echizen H., Drug. Metab. Dispos., 27,

1179-1186 (1999).

67) Takigawa T., Tainaka H., Mihara K., Ogata H., Biol. Pharm. Bull., 21,

541-543 (1998).

72

68) Matsumoto K., Ishida S., Ueno K., Hashimoto H., Takada M., Tanaka K.,

Kamakura S., Miyatake K., Shibakawa M., J. Clin. Pharmacol., 41, 459-464

(2001).

69) Osawa M., Hada N., Matsumoto K., Hasegawa T., Kobayashi D., Morimoto

Y., Yamaguchi M., Kanamoto I., Nakagawa T., Sugibayashi K., Int. J.

Pharm., 293, 43-49 (2005).

70) Diana F.J., Veronich K., Kapoor A.L., J. Pharm. Sci., 78, 195-199 (1989).

71) Chan T.Y., Lui S.F., Chung S.Y., Luk S., Critchley J.A., Drug. Saf., 10,

267-269 (1994).

72) Hossain M.K., Khatun A., Rahman M., Akter M.N., Chowdhury S.A., Alam

S.M., Adv. Pharm. Bull., 6, 589-595 (2016).

73) van Dijk K.N., Plat A.W., van Dijk A.A., Piersma-Wichers M., de

Vries-Bots A.M., Slomp J., de Jong-van den Berg L.T., Brouwers J.R.,

Thromb. Haemost., 91, 95-101 (2004).

74) Brouwers J.R., De Smet P.A., Clin. Pharmacokinet., 27, 462-485 (1994).

75) Harder S., Thurmann P., Clin. Pharmacokinet., 30, 416-444 (1996).

76) Haase K.K., Rojas-Fernandez C.H., Lane L., Frank D.A., Ann.

Pharmacother., 34, 666-667 (2000).

77) Stading J.A., Skrabal M.Z., Faulkner M.A., Am. J. Health. Syst. Pharm., 58,

2076-2080 (2001).

78) Sabbe J.R., Sims P.J., Sims M.H., Pharmacotherapy, 18, 871-873 (1998).

79) Scher M.L., Huntington N.H., Vitillo J.A., Ann. Pharmacother., 31, 646-647

(1997).