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Table 1 Patient characteristics at the start of sunitinib therapy

Patients

Age (years)

Gender: Female/Male

Body weight (kg)

17

62.0 (56.0–69.0)

6/11

58.8 (54.8–67.6)

Laboratory data

AST (IU/L)

18 (16–27)

ALT (IU/L)

19 (12–29)

eGFR (mL/min/1.73 m2)

52.4 (45.3–60.5)

Histology: Clear cell/Papillary

14/3

Performance status: 0–1/2–4

13/4

Number of prior systemic therapy: 0/≥1

12/5

Dose of sunitinib: 37.5 mg/25 mg

12/5

Data are expressed as the number of patients or median with the interquartile range in parentheses.

AST: aspartate aminotransferase, ALT: alanine aminotransferase, eGFR: estimated glomerular filtration rate

Table 2 Relationship between total sunitinib concentration and adverse effects

Total sunitinib concentration

All (n = 17)

< 108 ng/mL (n = 10)

≥ 108 ng/mL (n = 7)

ALT increase

4/3

2/1

2/2

AST increase

4/2

2/0

2/2

Hypertension

3/2

1/0

2/2

Diarrhea

3/1

0/0

3/1

GGT increase

2/1

1/0

1/1

Lipase increase

1/1

0/0

1/1

Oral mucositis

3/1

0/0

3/1

Platelet count decrease

7/1

4/0

3/1

Adverse effects

(All grades/Grade ≥ 3)

Data are expressed as the number of patients.

All adverse effects reported as grade 3 or higher in either group are shown.

Patients were counted once at the highest grade.

ALT: alanine aminotransferase, AST: aspartate aminotransferase, GGT: gamma-glutamyltransferase

Table 3 Relationship between sunitinib apparent oral clearance and patients’ characteristics

Sunitinib CL/F

All (n = 19)

< 15.3 L/h (n = 9)

≥ 15.3 L/h (n = 10)

61.0 (52.0–69.0)

68.0 (60.5–71.5)

56.0 (39.8–65.3)

0.08a)

7/12

4/5

3/7

0.43b)

59.5 (55.7–66.2)

60.5 (56.6–72.3)

59.2 (50.4–65.6)

0.32a)

AST (IU/L)

18 (16–28)

17 (16–27)

20 (17–35)

0.36a)

ALT (IU/L)

20 (12–34)

20 (13–28)

20 (11–36)

0.84a)

52.4 (46.1–60.9)

52.4 (45.3–57.6)

55.5 (47.6–65.8)

0.50a)

Histology: Clear cell/Papillary

16/3

8/1

8/2

0.54b)

Performance status: 0–1/2–4

14/5

7/2

7/3

0.56b)

Number of prior systemic therapy: 0/≥1

13/6

7/2

6/4

0.37b)

37.5 (25.0–37.5)

37.5 (25.0–37.5)

37.5 (25.0–37.5)

0.91a)

Age (years)

Gender: Female/Male

Body weight (kg)

Laboratory data

eGFR (mL/min/1.73 m2)

Dose of sunitinib (mg/day)

Data are expressed as the number of patients or median with the interquartile range in parentheses.

a) Mann–Whitney

U test. b) Fisher's exact test.

CL/F: apparent oral clearance, AST: aspartate aminotransferase, ALT: alanine aminotransferase, eGFR: estimated glomerular filtration rate

Fig. 1

(A) (B) p = 0.01

1.0

Sensitivity

Total sunitinib concentration

(ng/mL)

0.8

0.6

Cutoff value: 108 ng/mL

Sensitivity: 0.86 Specificity: 0.90

AUC-ROC: 0.87 p = 0.01

0.4

0.2

0.0

Severe adverse (－)

effects

(n = 10)

(＋)

(n = 7) 0.0

0.2

0.4

0.6

0.8

1 − Specificity

1.0

Fig. 2

(B)

1.0

1.0

0.8

Probability without treatment failure

Probability without dose reduction or withdrawal due to adverse effects

(A) p = 0.03

0.6

0.4

0.2

0.0

0.8

p = 0.61

0.6

0.4

0.2

0.0

50

100

150

200

250

300

350

100

Day after initiation of sunitinib (day)

200

300

400

500

600

Fig. 3

(A) (B) p = 0.01

Sunitinib CL/F (L/h)

1.0

Sensitivity

0.8

0.6

Cutoff value: 15.3 L/h

Sensitivity: 0.89 Specificity: 0.80

AUC-ROC: 0.83 p = 0.02

0.4

0.2

0.0

Severe adverse (－)

effects

(n = 10)

(＋)

(n = 9) 0.0

0.2

0.4

0.6

0.8

1 − Specificity

1.0

Fig. 4

(A) Sunitinib CL/F (L/h)

First CT scan Non-PD

(n = 15)

(B)

Probability of progression-free survival

p = 1.00

PD

(n = 4) 1.0

0.8

p = 0.77

0.6

0.4

0.2

0.0

100

200

300

400

500

600

700

Day after initiation of sunitinib (day)

Fig. 5

(B)

150

Onset of severe adverse effects

in patient 1

100

AST (grade 3)

ALT (grade 3)

50

150

Simulated sunitinib concentration

(ng/mL)

Sunitinib concentration

(ng/mL)

(A)

100

50

14

21

Day after initiation of sunitinib (day)

14

21

...