Table 3 Clinical pharmakokinetic profiles of TKI marketed in the EU
TKI | tmax(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. | 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 | ||