Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles.

摘要: Pyrimidine (imatinib, dasatinib, nilotinib and pazopanib), pyridine (sorafenib) pyrrole (sunitinib) tyrosine kinase inhibitors (TKIs) are multi-targeted TKIs with high activity towards several families of receptor non-receptor kinases involved in angiogenesis, tumour growth metastatic progression cancer. These orally administered have quite diverse characteristics regard to absorption from the gastrointestinal tract. Absolute bioavailability humans has been investigated only for imatinib (almost 100%) pazopanib (14–39%; n = 3). On basis human radioactivity data, dasatinib is considered be well absorbed after oral administration (19% 0.1% total were excreted as unchanged faeces urine, respectively). Quite low absolute under fasted conditions assumed (31%), sorafenib (50%) sunitinib (50%). Imatinib, exhibit dose-proportional increases their area plasma concentration-time curve values over therapeutic dose ranges. Less than observed at doses ≥400 mg/day ≥800 mg/day. At steady state, accumulation ratios 1.5–2.5 (unchanged imatinib), 2.0 (nilotinib once-daily dosing), 3.4 twice-daily 1.2–4.5 (pazopanib), 5.7–6.4 3.0–4.5 (sunitinib). Concomitant intake a high-fat meal does not alter exposure imatinib, but leads considerably increased decreased sorafenib. With exception pazopanib, described here large apparent volumes distribution, exceeding volume body water by least 4-fold. Very penetration into central nervous system reported there currently no published data nilotinib, or sunitinib. All that more 90% bound proteins: α1-acid glycoprotein and/or albumin. They metabolized primarily via cytochrome P450 (CYP) 3A4, being sorafenib, which uridine diphosphate glucuronosyltransferase 1A9 other main enzyme involved. Active metabolites contribute antitumour activity. Although some patient demographics identified significant co-factors partly explain interindividual variability TKIs, these findings regarded sufficient recommend age-, sex-, bodyweight-or ethnicity-specific adjustment. Systemic patients hepatic impairment, reduction initial recommended this subpopulation. The starting should also reduced renally impaired subjects. Because solubility pH dependent, co-administration histamine H2-receptor antagonists proton pump avoided. systemic significantly decreased/increased potent CYP3A4 inducers/inhibitors, so it strongly TKI adjusted such Caution substrates especially those narrow index. However, current recommendations adjustment need validated clinical studies. Further investigations needed pharmacokinetics drugs assess relevance interaction potential inhibitory effects on metabolizing enzymes transporters.