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

Abstract

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.

5-Fluorouracil sensitivity varies among oral micro-organisms

“…In the mouth, saliva levels during continuous infusion range from 0.08 to 0.8 µM (Joulia et al, 1999), hence significantly lower than what can be measured in plasma but still high enough to affect the most sensitive micro-organisms in the mouth. Furthermore, plasma concentrations can reach much higher concentrations in DPDdeficient patients due to the tenfold longer half-life time of 5-FU (Saif et al, 2009). …”

Therapeutic drug monitoring of 5-fluorouracil

“…Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goals of increasing clinical efficacy while reducing drug-associated toxicity [16, 17]. There is now convincing data showing that dose adjustment of 5-FU based on plasma 5-FU drug levels is feasible and that PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy.…”

Development and evaluation of nanostructured lipid carrier-based hydrogel for topical delivery of 5-fluorouracil

“…1 However, in each treatment, less-than-optimal delivery of 5-FU using conventional preparations such as creams and ointments have necessitated the use of more drastic measures to obtain therapeutic outcomes. 2 Pathogenesis of most skin diseases, such as psoriasis, cutaneous premalignant/malignant lesions and basal cell carcinoma in the epidermis, dermis, and deeper skin layers, dictates that the drug delivery strategy should be customized to localize high drug concentrations within the epidermis and dermis. 3 Currently, commercial formulations for topical 5-FU application are available in the form of solutions or creams at 0.5% 5-FU concentration for once-daily application (Carac ® ; Sanofi, Gentilly, France).…”