Clinical

British Journal of Cancer (2003) 89, 1855–1859. doi:10.1038/sj.bjc.6601152 www.bjcancer.com
Published online 11 November 2003

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia

This study was sponsored by Novartis Pharma AG. The study was presented in part at the 43rd Annual Meeting of the American Society of Hematology, 6–10 December 2001, Orlando, FL. Five authors (BP, CD, GM, SM and RC) are employees of Novartis Pharma AG

S G O'Brien1, P Meinhardt2, E Bond1, J Beck2, B Peng3, C Dutreix3, G Mehring3, S Milosavljev4, C Huber2, R Capdeville3 and T Fischer2

  1. 1Department of Haematology, University of Newcastle Medical School, Royal Victoria Infirmary, New Castle NE1 4LP, UK
  2. 2III. Med. Klinik und Poliklinik, Langenbeckstr, Mainz 155101, Germany
  3. 3Novartis Pharma AG, Basel, Switzerland
  4. 4Novartis Pharmaceuticals, East Hanover, NJ, USA

Correspondence: Dr SG O'Brien, E-mail: s.g.o'brien@ncl.ac.uk

Received 12 November 2002; Revised 14 April 2003; Accepted 25 May 2003.

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Abstract

The inhibition by imatinib of the cytochrome P450 3A4 isoenzyme may reduce the CYP3A4-mediated metabolic clearance of clinically important coadministered drugs. The main purpose of this study was to evaluate the effect of the coadministration of imatinib on the pharmacokinetics of simvastatin, a probe CYP3A4 substrate. In total, 20 patients with chronic myeloid leukaemia received an oral dose of 40 mg of simvastatin on study day 1. On study days 2–7, each patient received 400 mg of imatinib once daily orally and on study day 8, 400 mg imatinib together with 40 mg of simvastatin was given. Blood levels of simvastatin were measured predose and for 24 h postdose on study days 1 and 8. Two additional blood samples were taken for imatinib pharmacokinetic (PK) assessment on day 8 before, and 24 h after, imatinib administration. Imatinib increased the mean maximum concentration (Cmax) value of simvastatin two-fold and the area under concentration–time curve (AUC (0–inf)) value 3.5-fold (P<0.001) compared with simvastatin alone. There was a statistically significant decrease in total-body clearance of drug from the plasma (CL/F) with a mean reduction of 70% for simvastatin (P<0.001): the mean half-life of simvastatin was prolonged from 1.4–2.7 h when given together with imatinib. No changes in imatinib PK parameters were found when given concomitantly with simvastatin. In conclusion, the coadministration of imatinib at steady state with 40 mg simvastatin increases the exposure (Cmax and AUCs) of simvastatin significantly (P<0.001) by two-three-fold. Caution is therefore required when administering imatinib with CYP3A4 substrates with a narrow therapeutic window. The coadministration of simvastatin with imatinib (400 mg) was well tolerated and no major safety findings were reported in this study.

Keywords:

imatinib, Glivec, Gleevec, CML, simvastatin, pharmacokinetics, cytochrome P450, CYP3A4