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 Therapeutic drug monitoring (TDM) 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".

Clinical trials

Here some additional information about our main ongoing clinical trials:

• Imatinib Concentration Monitoring Evaluation (I-COME)

Bibliography

Our main publications (original and review articles) on this research area are:

Clinical research

• Gotta V, Widmer N, Montemurro M, Leyvraz S, Haouala A, Decosterd LA, Csajka C, Buclin T. Therapeutic drug monitoring of imatinib: Bayesian and alternative methods to predict trough levels. Clin Pharmacokinet 2011 [in press].
• von Mehren M, Widmer N. Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing? Cancer Treat Rev 2011;37(4):291-299. PMID: 21078547.
• Buclin T, Widmer N, Biollaz J, Decosterd LA. Who is in charge of assessing therapeutic drug monitoring? The case of imatinib. Lancet Oncol 2011;12(1): 9-11. PMID: 21111679.
• Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 2011;117(8):e75-e87. PMID: 20810928.
• Widmer N, Gotta V, Haouala A, Decosterd LA. Tyrosine kinase inhibitors concentration monitoring in chronic myeloid leukemia. Leuk Res 2010;34(6):698-9. PMID: 20074797.
• Gotta V, Widmer N, Decosterd LA, Csajka C, Duchosal MA, Chalandon Y, Heim D, Gregor M, Buclin T. Therapeutisches Drug-Monitoring von Imatinib. Schweiz Med Forum 2010;10(23):403–406.
• Widmer N, Decosterd LA, Csajka C, Montemurro M, Haouala A, Leyvraz S, Buclin T, Imatinib plasma levels: correlation with clinical benefit in GIST patients. Br J Cancer 2010;102(7):1198-1199. PMID: 20179709.
• Haouala A, Zanolari B, Rochat B, Montemurro M, Zaman K, Duchosal MA, Ris HB, Leyvraz S, Widmer N, Decosterd LA. Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877(22):1982-96. PMID: 19505856.
• Widmer N, Decosterd LA, Leyvraz S, Duchosal M.A, Rosselet A, Debiec-Rychter M, Csajka C, Biollaz J, Buclin T. Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability. Br J Cancer 2008;98(10):1633-1640. PMID: 18475296.
• Widmer N, Decosterd LA, Csajka C, Leyvraz S, Duchosal MA, Rosselet A, Rochat B, Eap CB, Henry H, Biollaz J, Buclin T. Population pharmacokinetics of imatinib and the role of alpha-1-acid glycoprotein. Br J Clin Pharmacol 2006;62(1):97-112; erratum Br J Clin Pharmacol 2010;70(2):316. PMID: 16842382.
• Widmer N, Beguin A, Rochat B, Buclin T, Kovacsovics T, Duchosal MA, Leyvraz S, Rosselet A, Biollaz J, Decosterd LA. Determination of imatinib (Gleevec) in human plasma by solid-phase extraction-liquid chromatography-ultraviolet absorbance detection. J Chromatogr B Analyt Technol Biomed Life Sci 2004;803(2):285-292. PMID: 15063337.

Cellular research

• Haouala A, Rumpold H, Untergasser G, Buclin T, Ris HB, Widmer N, Decosterd LA, siRNA-mediated knock-down of P-glycoprotein expression reveals distinct cellular disposition of anticancer tyrosine kinases inhibitors. Drug Metab Lett 2010;4(2):114-119. PMID: 20446917.
• Widmer N, Rumpold H, Untergasser G, Fayet A, Buclin T, Decosterd LA. Resistance reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels. Leukemia 2007;21(7):1561-2; author reply 1562-4. PMID: 17429432.
• Widmer N, Colombo S, Buclin T, Decosterd LA. Functional consequence of MDR1 expression on imatinib intracellular concentrations. Blood 2003;102(3):1142. PMID: 12869489.