Thus, safety-and efficacy profile have

to be taken into account. Most conventional cytotoxic medicinal products are given parenterally for a short duration in repeated cycles. They are mostly dosed on an individual basis (e.g. body surface or weight). The recommended dose is normally the maximum tolerated dose (MTD) or close to it. Marketed TKI drugs are typically given continuously via the oral route and at a flat dose. Although a most effective and durable target saturation is the primary objective for dose development of TKI drugs, it is obvious that for several TKI drugs the recommended dose is the same as the reported MTD, e.g. Bosutinib, Pazopanib, Ponatinib or Sunitinib (Table 3). The dose-limiting toxicities include grade 3 gastrointestinal and hepatic toxicities, grade 3 skin toxicities, grade 3 fatigue, and grade 3 hypertension. For Sunitinib grade 2 bullous selleck screening library skin toxicity, grade 3 fatigue, and grade 3 hypertension are reported as dose-limiting toxicities. Furthermore, at approx. twice the therapeutic concentration a grade 2 QT-prolongation is expected (Summary of Product Characteristics/SmPC Sutent® [16]). Table 3 Clinical

pharmakokinetic profiles of TKI marketed in the EU TKI tmax(h) Bioavailability (oral, %) Selleckchem PF477736 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, Eltanexor CYP2D6, CYP3A5 (possibly CYP1A1) NorGefitinib (M523595) Ponatinib 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.