Cancer Chemotherapy and Pharmacology

, Volume 53, Issue 2, pp 102–106

Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects

  • Ann E. Bolton
  • Bin Peng
  • Martine Hubert
  • Axel Krebs-Brown
  • Renaud Capdeville
  • Urs Keller
  • Michael Seiberling
Original Article



This study was carried out to investigate the influence of CYP3A induction with rifampicin on imatinib (Gleevec) exposure.


The study employed a single center, single-sequence design. A group of 14 healthy male and female subjects received imatinib as a single 400 mg oral dose on two occasions: on study day 1 and on study day 15. Rifampicin treatment (600 mg once daily) for CYP4503A induction was initiated on study day 8 and maintained until day 18. Imatinib pharmacokinetics were determined up to 96 h after dosing on day 1 (no induction) and on days 15–18 (during concomitant rifampicin). Plasma concentrations of imatinib and its main metabolite CGP74588 were determined using a LC/MS/MS method. The ratio of 6β-hydroxycortisol to cortisol excreted in the urine was measured to monitor the induction of CYP3A.


During concomitant rifampicin administration, the mean imatinib Cmax, AUC0–24 and AUC0–∞ decreased by 54% (90% CI: 48–60%), 68% (64–70%) and 74% (71–76%), respectively. The increase in clearance (Cl/f) was 385% (348–426%) during rifampicin treatment. The mean Cmax and AUC0–24 of the metabolite CGP74588 increased by 88.6% (68.3%–111.4%) and 23.9% (13.5%–35.2%) after rifampicin pretreatment. However, the AUC0–∞ decreased by 11.7% (3.3–19.4%). All subjects demonstrated a marked induction of hepatic microsomal CYP3A analyzed by the excretion ratio of 6β-hydroxycortisol to cortisol from a mean baseline concentration of 5.6 U to 50.5 U.


Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.


Imatinib Rifampicin CYP3A Drug interaction 


  1. 1.
    Combalbert J, Fabre I, Fabre G, Dalet I, Derancourt J, Cano JP, Maurel P (1989) Metabolism of cyclosporin A. IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin A oxidase) as a product of P450IIIA gene subfamily. Drug Metab Dispos 17:197–207PubMedGoogle Scholar
  2. 2.
    Demetri GD, Von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveswon DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Drucker BJ, Corless C, Fletcher CDM, Joensuu H (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480Google Scholar
  3. 3.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon N, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers S (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037PubMedGoogle Scholar
  4. 4.
    electronic Medicines Compendium (2003) Scholar
  5. 5.
    Ged C, Rouillon JM, Pichard L, Combalbert, Bressot N, Bories P, Michel H, Beaune P, Maurel P (1989) The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br J Clin Pharmacol 28:373–387Google Scholar
  6. 6.
    Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman SL. Capdeville R, Dimitrijevic S, Drucker B Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056PubMedGoogle Scholar
  7. 7.
    Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Drucker B (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myeloid leukemia. N Engl J Med 346:645–652PubMedGoogle Scholar
  8. 8.
    Kovacs SJ, Martin DE, Everitt DE, Patterson SD, Jorkasky DK (1998) Urinary excretion of 6 β-hydroxycortisol as an in vivo marker for CYP3A4 induction: applications and recommendations. Clin Pharmacol Ther 63:617–622PubMedGoogle Scholar
  9. 9.
    Novartis Pharmaceuticals Corporation (2002) Gleevec imatinib mesylate: full prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJGoogle Scholar
  10. 10.
    O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Somonsson B, Gratwhol A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Drucker B (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004CrossRefPubMedGoogle Scholar
  11. 11.
    Reichel C, Block W, Skodra T, Träber F, Scheidermaier P, Spengler U, Nuber R, Schild H, Sauerbruch T (1979) Relationship between cytochrome P-450 by rifampin, hepatic volume and portal blood flow in man. Eur J Gastroenterol Hepatol 9:975–979Google Scholar
  12. 12.
    Sawyers CL, Hocchaus A, Feldman E, Goldman CL, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MWN, Fischer T, O’Brien SG, Stone RM, Gambacorti-Passerini CB, Russell NH, Reiffers JJ, Shea TC, Chapius B, Coutre S, Tura S, Morra E, Larson RA, Saven A, Peschel C, Gratwhol A, Mandelli F, Ben-Am M, Gathmann I, Capdeville R, Paquette RL, Drucker BJ (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myeloid leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539CrossRefPubMedGoogle Scholar
  13. 13.
    Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini CB, Guilhot F, Schiffer CA, Fischer T, Deininger MWN, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon F, Ferrnandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyer CL (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia. Blood 99:1928–1937CrossRefPubMedGoogle Scholar
  14. 14.
    Tran JQ, Kovacs SJ, McIntosh TS, Davis HM, Martin DE (1999) Morning spot and 24-hour urinary 6β-hydroxycortisol to cortisol ratios: intraindividual variability and correlation under basal conditions and conditions of CYP 3A4 induction. J Clin Pharmacol 39:487–494PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Ann E. Bolton
    • 1
    • 5
  • Bin Peng
    • 2
  • Martine Hubert
    • 3
  • Axel Krebs-Brown
    • 1
  • Renaud Capdeville
    • 1
  • Urs Keller
    • 4
  • Michael Seiberling
    • 4
  1. 1.Novartis Pharma AGBaselSwitzerland
  2. 2.Novartis Pharmaceuticals Corp.East HanoverUSA
  3. 3.Novartis Pharma SASRueil-Malmaison CedexFrance
  4. 4.Swiss Pharma Contract Ltd.AllschwilSwitzerland
  5. 5.Oncology Business UnitNovartis Pharma AGBaselSwitzerland

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