Current status and future outlooks on therapeutic drug monitoring of fluorouracil

ABSTRACT

Introduction

Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied.

Areas covered

This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine.

Expert opinion

New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Preemptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.

KEYWORDS:

• Chemotherapy
• fluorouracil
• pharmacodynamics
• pharmacogenetics
• pharmacokinetics
• therapeutic drug monitoring

Article highlights

• Fluorouracil (5FU) pharmacokinetics (PK) is characterized by a large inter-individual variability which might be partially explained by the status of the main metabolizing enzyme dihydropyridimidine dehydrogenase (DPD). Traditional dosing by body surface area is not able to substantially reduce this variability. Therapeutic drug monitoring (TDM) is a well-researched method to significantly reduce PK variability and improve the efficacy and safety of 5FU therapy.

• Despite the wide availability of favorable evidence in support of 5FU-TDM it is not fully established yet in clinical routine. To date, only preemptive pharmacogenetic testing of DPD status is routinely performed.

• Newly performed studies further strengthen the evidence to apply 5FU-TDM. In addition, a combination of DPD testing and TDM showed promising results in order to further improve the benefit-risk ratio of 5FU-based treatment.

• Pharmacometric models combining PK and pharmacodynamics of 5FU have a large potential to further optimize chemotherapy. 5FU-TDM can potentially assist in model development and improve individual predictions on the future drug exposure.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.