Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib

N. P. van Erp, H. Gelderblom, M. O. Karlsson, J. Li, M. Zhao, J. Ouwerkerk, J. W. Nortier, H.-J. Guchelaar, S. D. Baker, A. Sparreboom
2007 Clinical Cancer Research  
Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. Experimental Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day1) and on the third day (day 4).The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on
more » ... f imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. Results: In 11evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days1and 4 were 42.6 (33.0-54.9) AgÁh/mL and 41.2 (32.1-53.1) AgÁh/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 Amol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro.
doi:10.1158/1078-0432.ccr-07-0346 pmid:18094422 fatcat:px7mu5ytzjhj7os2dmfyigenny