Table 3.
Clinical pharmakokinetic profiles of TKI marketed in the EU
| TKI | t max (h) | Bioavailability (oral, %) | Concomitant food intake effect on bioavailability | Concomitant food intake: FDA recommendation | V (L/kg) 70-kg subject assumed | Primary enzymes involved in metabolism | Major metabolites | Plasma half-life (h) | Plasma protein binding (%) | Suggested threshold for response or concentration attained in therapy (mg/L) |
|---|---|---|---|---|---|---|---|---|---|---|
| Bosutinib |
6 |
18 [20] derived from colon tumor xenograft models |
|
With food |
131-214 [21] |
CYP3A4 |
M2 (oxydechlorinated Bosutinib) M5 (N-desmethyl Bosutinib) |
|
94-96 |
|
| Dasatinib |
0.5–3 |
<34 |
Increases AUC (14%) |
With/without food |
30-40 |
CYP3A4, FMO-3 |
M4 (BMS-582691), M5 (BMS-606181), M6 (BMS-573188) |
3–5 |
92–97 |
0.01–0.1 [22] |
| Erlotinib |
4 |
69-76 |
Increases bioavailability (24%–31%) |
Without food |
3 |
CYP3A4, CYP3A5, CYP1A2 |
NorErlotinib (OSI-420) |
41 |
92-95 |
>0.5 |
| Gefitinib |
3-7 |
57 |
No effect |
With/without food |
24 |
CYP3A4, CYP2D6, CYP3A5 (possibly CYP1A1) |
NorGefitinib (M523595) |
48 |
79 |
>0.2 |
| Imatinib |
2–4 |
98 |
No effect |
With food |
2–6 (Imatinib), 15–40 (NorImatinib) |
CYP3A4, CYP3A5, CYP2C8 |
NorImatinib (CGP74588) |
12–20 (Imatinib), 40–74 (NorImatinib) |
95 (Imatinib and NorImatinib) |
>1 (CML and GIST) |
| Lapatinib |
3-5 |
- |
Increases AUC (167%–325%) |
Without food |
31 |
CYP3A4, CYP3A5 |
Norlapatinib (GW690006) |
14 |
>99 |
>0.5 mean concentration in patients prescribed 1500 mg once daily [23] |
| Nilotinib |
3 |
30 |
Increases Cmax (112%) and AUC (82%) |
Without food |
10–15 |
CYP3A4, CYP2C8 |
- |
15–17 |
98 |
>0.6 Cmin concentration applicable to quartile 1 from cytogenetic response [24] |
| Pazopanib |
2.8 |
14-39 |
Increases AUC and Cmax (2-fold) |
Without food |
0.1-0.2 |
CYP3A4, CYP1A2, CYP2C8 |
Pazopanib M24, Pazopanib M26, Pazopanib M27 |
31 |
>99 |
>20 |
| Ponatinib |
|
|
|
With/without food |
|
CYP3A4 (MRI PI) |
inactive carboxylic acid |
|
>99 |
|
| Sorafenib |
2-14 |
<50 |
Reduces bioavailability (29%) |
Without food |
3-6 |
CYP3A4, UGT1A9 |
Norsorafenib, Sorafenib N-oxide (BAY 67 3472) |
20-40 |
>99 |
>3 |
| Sunitinib |
6-12 |
- |
No effect |
With/without food |
30 |
CYP3A4 |
Norsunitinib (SU12662) |
40–60 (Sunitinib), 80–110 (Norsunitinib) |
95 (Sunitinib), 90 (Norsunitinib) |
>0.05 (Sunitinib + Norsunitinib) |
|
TKI |
DLT |
MTD |
Clinical dose (as recommended by SmPC) |
Dosage form |
Human AUC at the clinical dose (ng*h/ml) |
In vitro IC
50
values for target kinase inhibitor (ng/ml) |
Dose-reduction |
|||
|
Liver |
renal |
|||||||||
| Bosutinib |
Grade 3 diarrhea, grade 3 rash [25] |
500 mg, q.d |
500 mg, q.d. |
Tablet |
2740 ± 790 |
250 nM [26] |
|
Yes |
||
| Dasatinib |
Grade 3 nausea, grade 3 fatigue, grade 3 rash [27] |
>120 mg b.i.d |
100 mg, q.d. (for chronic phase), 70 mg, b.i.d. (for accelerated phase and blast phase) |
Tablet |
398.8 (b.i.d. regimen) |
0.0976 |
No, only in severe liver impairment |
No |
||
| Erlotinib |
Diarrhea [28] |
150 mg, q.d. |
150 mg, q.d. |
Tablet |
42679 |
0.787 [29] |
No |
No |
||
| Gefitinib |
Nausea, diarrhea, vomiting, rash |
700 mg, q.d. |
250 mg, q.d. |
Tablet |
7251.5 |
12.1 [30] |
No, only in severe liver impairment |
No |
||
| Imatinib |
Nausea, vomiting, fatigue, diarrhea |
>1000 mg, b.i.d. |
400 mg, q.d |
Tablet |
33200 |
12.3 [31] |
Yes |
No |
||
| Lapatinib |
Rash, diarrhea, fatigue |
1800 mg, q.d. |
1250 mg, q.d. |
Tablet |
33836.5 |
6.02 [32] |
Yes |
No, only in severe renal impairment |
||
| Nilotinib |
Liver function abnormalities, thrombocytopenia [33] |
600 mg, b.i.d. |
400 mg, b.i.d. (for chronic-phase and accelerated-phase of chronic myelogenous leukemia), 300 mg, b.i.d. (for newly diagnosed chronic-phase myelogenous leukemia) |
Capsule |
19000 (b.i.d. regimen) |
not available |
No |
No |
||
| Pazopanib |
Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations, grade 3 malaise [34] |
800 mg, q.d. [35,36] |
800 mg, q.d. |
Tablet |
650 ± 500 μg*h/ml |
10, 30, 47, 71, 84 or 74 nM |
Yes |
No |
||
| Ponatinib |
Rash, fatigue |
45 mg, q.d |
45 mg, q.d. |
Tablet |
77 (50%) or 1296 (48%) |
0.4 or 2.0 nM |
Yes |
No |
||
| Sorafenib |
Hand-foot skin syndrome (HFS) [37] |
600 mg, b.i.d. |
400 mg, b.i.d. |
Tablet |
36690 (b.i.d. regimen) |
7.79 [38] |
No |
No |
||
| Sunitinib | Grade 3 fatigue, grade 3 hypertension, grade 2 bullous skin toxicity (HFS) [39] | 50 mg, q.d. | 50 mg, q.d. | Capsule | 1406 | 0.797 | No, only in severe liver impairment | No | ||
AUC, area under the curve; b.i.d., twice daily; DLT, dose limiting toxicity; MTD, maximum tolerated dose; q.d., every day; tmax, time after administration when Cmax is reached; Source of information: Summaries of Product Characteristics (SmPCs) of marketed TKI [16] unless otherwise indicated.