Drug delivery of oral anti-cancer fluoropyrimidine agents

ABSTRACT

Introduction: Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules.

Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs.

Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.

KEYWORDS:

• Anti-cancer fluoropyrimidine agent
• dihydropyrimidine dehydrogenase inhibitor
• FDA approval
• fixed-dose combination drug
• oral administration
• prodrug

Article highlights

• 5-FU is a time-dependent anti-cancer drug but is short-acting in plasma due to its rapid degradation by dihydropyrimidine dehydrogenase; as such, the approach to add dihydropyrimidine dehydrogenase inhibitors to 5-FU regimens would enhance 5-FU efficacy in cancer treatment.

• To improve the anti-cancer activity of 5-FU, minimize its toxicity, and overcome problems and complications arising from 5-FU infusion regimens, inactive 5-FU prodrugs were developed as oral formulations, which are gradually absorbed via the gastrointestinal tract, converted into the active form in the systemic circulation, and released into the plasma to maintain sustained 5-FU concentrations.

• Oral 5-FU prodrugs have been combined with or attempted to be combined with dihydropyrimidine dehydrogenase inhibitors such as uracil into fixed-dose combination drugs along with potassium oxonate or biochemical modulators such as leucovorin.

• To further improve the efficacy of 5-FU, the administration schedule of oral 5-FU prodrugs can be modified to minimize 5-FU-free intervals in each therapeutic cycle, since 5-FU is a time-dependent drug.

• Many regimens that include infusional 5FU schedules for several days to weeks can be replaced with oral 5-FU prodrugs, and with the above modifications, improved anti-cancer efficacy may be achieved.

• Patients would benefit from the development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.

This box summarizes key points contained in the article.

Declaration of interest

Two studies introduced in this review [89,94] were supported by the Osaka Basic Medical Research Foundation (Osaka, Japan). The authors have no other 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 apart from those disclosed.

Additional information

Funding

No funding was received for the preparation of this manuscript