Clinical pharmacology of new anticancer agents

While most current chemotherapy regimens are administered through short i.v. cycles, targeted TKI drugs such as imatinib are administered orally and must be taken indefinitely. Moreover, they are extensively metabolized by cytochromes P450, whose activity is characterized by a large degree of inter-individual variability. Imatinib is also a substrate of drug transporters such as P-glycoprotein (P-gp) and organic cation transporter 1 (hOCT1), and is bound to circulating alpha-1-acid glycoprotein (AGP) in the plasma (only a small free fraction is thus responsible of the therapeutic action).

A given dose of TKI can therefore yield very different circulating concentration profiles from one patient to another, thus favoring the selection of resistant cellular clones in case of sub-therapeutic drug exposure, or the occurrence of undesirable toxicity in case of overexposure. As confirmed by recent evidence, serious adverse events are rather rare under imatinib at usual dosage, but moderate symptoms of poor tolerance are not infrequent, and while generally considered as acceptable for a limited treatment period they may significantly impact on quality of life during chronic therapy, Moreover, the occurrence and severity of adverse effects is clearly dose-dependent, and may thus reveal even better correlated with concentration exposure.

In our Division of Clinical Pharmacology and Toxicology we are thus performing research on the clinical pharmacokinetics of these new anticancer agents, together with research on the clinical benefit of a research on the clinical pharmacokinetics program for the patients treated with these drugs. Finally, we are also interested in the disposition of TKIs in cancer cells, in the context of a new research field named "cellular pharmacokinetics".

Here some additional information about our main ongoing clinical trial (recruitment closed, results awaited soon) :

• Imatinib Concentration Monitoring Evaluation (I-COME)