Overcoming barriers to implementing precision dosing with 5‐fluorouracil and capecitabine

Abstract

Despite advances in targeted cancer therapy, the fluoropyrimidines 5-fluorouracil (5FU) and capecitabine continue to play an important role in oncology. Historically, dosing of these drugs has been based on body surface area. This approach has been demonstrated to be an imprecise way to determine the optimal dose for a patient. Evidence in the literature has demonstrated that precision dosing approaches, such as DPD enzyme activity testing and, in the case of intravenous 5FU, pharmacokineticguided dosing, can reduce toxicity and yield better patient outcomes. However, despite the evidence, there has not been uniform adoption of these approaches in the clinical setting. When a drug such as 5FU has been used clinically for many decades, it may be difficult to change clinical practice. With the aim of facilitating change of practice, issues and barriers to implementing precision dosing approaches for 5FU and capecitabine are identified and discussed with possible solutions proposed.

In vitro co-culture systems of hepatic and intestinal cells for cellular pharmacokinetic and pharmacodynamic studies of capecitabine against colorectal cancer

“…The expression of TP is significantly higher and the expression of DPD is lower in tumor cells than in normal cells, which contributes to the tumor-specific conversion and targeted intra-tumoral cytotoxicity of CAP [ 26 – 28 ]. Given this tumor-targeting performance, CAP has been demonstrated to produce a lower incidence of serious adverse events (such as neutropenia, nausea, and emesis) than intravenous 5-FU based chemotherapy regimens, although hand-foot syndrome (HFS) and hyperbilirubinemia are more frequently observed with CAP treatment [ 29 , 30 ].…”

“…Only 20–30% of patients receiving intravenous 5-FU achieved plasma 5FU concentrations in the appropriate therapeutic range, approximately 40–60% of patients were underdosed and 10–20% overdosed. The 5-FU tissue concentrations were at least 10 times higher than the plasma concentrations after 5-FU treatment based on BSA within 48 h, and 5-FU was retained for a much more extended time in tissues than in plasma [ 26 , 30 , 31 ]. Moreover, patients with CRC who experienced skeletal muscle mass (SMM) loss during CAP treatment were at an increased risk of developing severe toxicity and had shorter survival time [ 32 ].…”

“…For drugs with intracellular targets, such as CAP and 5-FU, it is more critical to explore drug concentrations in cells/subcellular organelles over time than in plasma. It has been evidenced that precise dosing methods, such as DPD enzyme activity testing and, in the case of intravenous 5-FU, PK guided dosing, could reduce toxicity and produce better patient prognosis [ 30 ].…”

Precision medicine‐based drug treatment individualization in oncology

“…Exploring the relationship between 5-FU area under the curve (AUC) and a target dose resulted in the recommendation of a therapeutic exposure range of 20-30 mgh/L for 46-h infusion schedules. 19 Unfortunately, data are lacking to apply TDM dosing to the oral prodrug capecitabine, which is just as effective as 5-FU but better tolerated.…”

Editorial for the “Precision Medicine-based Drug Treatment Individualization in Oncology” themed issue Precision Medicine-based Drug Treatment Individualization in Oncology - THEMED ISSUE EDITORAL

“…In articulating the importance of TDM dosing Schneider JJ et al in this themed issue, reiterate that 5-FU dosing by BSA only results in 20-30% patients achieving the therapeutic range. Exploring the relationship between 5-FU area under the curve (AUC) and a target dose resulted in the recommendation of a therapeutic exposure range of 20-30mgh/L for 46-hour infusion schedules (20). Unfortunately, data is lacking to apply TDM dosing to the oral prodrug capecitabine, which is just as effective as 5-FU but better tolerated.…”