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Journal of the National Cancer Institute Advance Access published online on October 19, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp328
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© The Author 2009. Published by Oxford University Press.

REVIEW

Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil: A Rational Approach to Improving Therapeutic Outcomes

M. Wasif Saif, Adrienne Choma, Salvatore J. Salamone, Edward Chu

Affiliations of authors: Developmental Therapeutics Program, Yale Cancer Center, Yale University School of Medicine, New Haven, CT (MWS, EC); Saladax Biomedical Inc, Bethlehem, PA (AC, SJS)

Correspondence to: M. Wasif Saif, MD, Section of Medical Oncology, Yale University School of Medicine, 333 Cedar St, FMP 116, New Haven, CT 06520 (e-mail: wasif.saif{at}yale.edu).

Chemotherapy dosing of the fluoropyrimidine 5-fluorouracil (5-FU) is currently based on body surface area. However, body surface area–based dosing has been associated with clinically significant pharmacokinetic variability, and as such, dosing based on body surface area may be of limited use. The clinical activity of 5-FU is modest at standard doses, and in general, dosing is limited by the safety profile, with myelosuppression and gastrointestinal toxicity being the most commonly observed side effects. Various strategies have been developed to enhance the clinical activity of 5-FU, such as biochemical modulation, alterations in scheduling of administration, and the use of oral chemotherapy. Studies that have shown an association between plasma concentration with toxicity and clinical efficacy have shown that pharmacokinetically guided dose adjustments can substantially improve the therapeutic index of 5-FU treatment. These studies have shown that only 20%–30% of patients treated with a 5-FU–based regimen have 5-FU levels that are in the appropriate therapeutic range—approximately 40%–60% of patients are underdosed and 10%–20% of patients are overdosed. To date, 5-FU drug testing has not been widely used because of the lack of a simple, fast, and inexpensive method. Recent advances in testing based on liquid chromatography–mass spectroscopy and a nanoparticle antibody–based immunoassay for 5-FU may now allow for routine monitoring of 5-FU in clinical practice. We review the data on pharmacokinetically guided dose adjustment of 5-FU and discuss the potential of this approach to advance therapeutic outcomes.

Manuscript received November 17, 2008; revised August 11, 2009; accepted August 17, 2009.


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J Natl Cancer Inst 2009 101: 1523. [Extract] [Full Text] [PDF]





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