Although rigorous scientific basis for the use of body surface area (BSA), expressed as mg/m2, outside of early-phase clinical trials assessing the maximum tolerated dose, is lacking, most antineoplastic agents are dosed by this method. The same calculation is used for all patients, regardless of the possibility of individual metabolism of a particular drug. For some therapeutic agents, specifically 5-fluorouracil (5-FU), this system may result in an inaccurate dose. There is wide variability in plasma 5-FU levels (levels may vary by 100-fold). Interpatient and intrapatient pharmacokinetic variability is a major contributor to toxicity and treatment failure.
Saif and colleagues1 published a review of the rationale for pharmacokinetically guided monitoring of 5-FU dosing in which they present many pharmacokinetic variations in any particular patient that may affect the clinical efficacy and side effect profile of 5-FU:
Figure 1. Potential Pharmacokinetic Variations
|
Pharmacogenetic Factors
? Absorption
? Distribution
? Metabolism
? Excretion |
|
Other Factors
? Performance status
? Age
? Sex
? Weight
? Circadian diurnal variation |
|
Drug-Specific Factors
? Dietary status
? Food-drug interactions
? Drug-drug interactions
? Compliance with oral agents |
Other topics covered in this review article include:
- Establishing Target AUCs with the Newer Infusion Regimens
- Clinical Value of Pharmacokinetically Guided 5-FU Dose Management
- Dose Management to Improve Clinical Efficacy and Safety Profile
- Dihydropyrimidine dehydrogenase deficiency (DPD Deficiency)
- Role of Thymidylate Synthase
- Role of Circadian Variation
- Economic Importance of Pharmacokinetically Based 5-FU Dosing
In 2008, a phase III randomized study of 208 metastatic colorectal cancer (mCRC) patients by Gamelin et al3 found that mCRC patients whose dose of 5-fluorouracil (5-FU) was personalized based on results of regular blood tests experienced reduced severe toxicities and nearly doubled response rates compared to patients who received standard 5-FU dosing based on body surface area. Additionally, patients who received personalized dosing experienced a 48% relative improvement in survival at two years. The Gamelin et al study demonstrated that only 25% of CRC patients achieved optimal chemotherapy blood levels when dosed by BSA. Seventeen percent of the BSA-dosed patients received toxic levels of the drug, while 58% were under-dosed.3
Future research into the role of therapeutic drug monitoring as it relates to 5-FU therapy will be assessed in a prospective randomized clinical trial using the mFOLFOX7 regimen plus bevacizumab in first-line treatment of metastatic CRC. The goal of the study will be to provide further support for the use of pharmacokinetically guided 5-FU dose adjustment in clinical practice.1 A similar trial is already underway in Singapore http://clinicaltrials.gov/ct2/show/NCT00943137.
References
- Saif MW, Choma A, Salamone SJ, Chu E. Pharmacokinetically guided dose adjustment of 5-fluorouracil: A rational approach to improving therapeutic outcomes. J Natl Cancer Inst. 2009; 101:1543-1552. doi: 10.1093/jnci/djp328 Link to abstract http://jnci.oxfordjournals.org/cgi/content/short/101/22/1543
- Beumer JH , Boisdron-Celle M , Clarke W , et al. Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the Olympus AU400 analyzer. Ther Drug Monit. 2009; 31:688-694. doi: 10.1519/JSC.0b013e3181b866d0 Link to abstract on PubMed http://www.ncbi.nlm.nih.gov/pubmed/19745790
- Gamelin E, Jacob J, Merrouche Y, et al. Individual 5-fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: Results of a multicenter randomized trial in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26: 2099–2105. doi: 10.1200/JCO.2007.13.3934 Link to abstract http://jco.ascopubs.org/cgi/content/abstract/26/13/2099.