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The effect of rifampicin, a prototypical CYP3A4 inducer, on erlotinib pharmacokinetics in healthy subjects

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Abstract

Purpose

Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co-administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib.

Methods

Study 1 included Groups A (erlotinib 150 mg days 1 and 15, rifampicin 600 mg days 8–14) and B (erlotinib 150 mg days 1 and 15) in a parallel group study design. Study 2 subjects received erlotinib 150 mg day 1, erlotinib 450 mg day 15, and rifampicin 600 mg days 8–18. The primary endpoint in each study was the ratio of exposure (AUC0–∞ and C max) between days 1 and 15. Urinary cortisol metabolic induction ratios were determined in Study 1 for Group A subjects only.

Results

In Study 1, the geometric mean ratios of AUC0–∞ and C max were 33 and 71 %, respectively, and the mean cortisol metabolic index increased from 7.4 to 27.0, suggesting cytochrome P450 (CYP) enzyme induction. In Study 2, the geometric mean ratios for AUC0–∞ and C max were 19 and 34 % (when dose adjusted from 450 to 150 mg erlotinib), respectively, a greater relative decrease than observed in Study 1.

Conclusions

Erlotinib exposure (AUC0–∞ and C max) was reduced after pre- or concomitant dosing with rifampicin. Doses of ≥450 mg erlotinib may be necessary to compensate for concomitant medications with strong CYP3A4 enzyme induction effect.

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Acknowledgments

Funding for the clinical studies described was provided by F-Hoffman La Roche (Study 1) and OSI Pharmaceuticals Inc (Study 2).

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Authors and Affiliations

  1. The Hamilton Consulting Group, Boulder, CO, USA

    Marta Hamilton

  2. Novella Clinical Research, Boulder, CO, USA

    Julie L. Wolf

  3. Somalogic, Boulder, CO, USA

    Daniel W. Drolet

  4. Hoffman La Roche, Nutley, NJ, USA

    Scott H. Fettner

  5. Forest Research Institute, Jersey City, NJ, USA

    Ashok K. Rakhit

  6. KW Biotech Consulting, Boulder, CO, USA

    Karsten Witt

  7. Department of Clinical Pharmacology, Development Sciences, Genentech Research and Early Development, Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA

    Bert L. Lum

Authors
  1. Marta Hamilton
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  2. Julie L. Wolf
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  3. Daniel W. Drolet
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  4. Scott H. Fettner
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  5. Ashok K. Rakhit
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  6. Karsten Witt
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  7. Bert L. Lum
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Correspondence to Bert L. Lum.

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Hamilton, M., Wolf, J.L., Drolet, D.W. et al. The effect of rifampicin, a prototypical CYP3A4 inducer, on erlotinib pharmacokinetics in healthy subjects. Cancer Chemother Pharmacol 73, 613–621 (2014). https://doi.org/10.1007/s00280-014-2390-3

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  • DOI: https://doi.org/10.1007/s00280-014-2390-3

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