Skip to main content

Table 3 Clinical pharmakokinetic profiles of TKI marketed in the EU

From: Clinical pharmacology of tyrosine kinase inhibitors becoming generic drugs: the regulatory perspective

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. [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
  1. 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.