Trifluridine/tipiracil

Trifluridine/tipiracil

Combination of
Trifluridine	Cytotoxin
Tipiracil	Thymidine phosphorylase inhibitor
Clinical data
Trade names	Lonsurf
Pregnancy category	Can cause fetal harm
Legal status	US: ℞-only
Identifiers
CAS Number	733030-01-8

Trifluridine/tipiracil (trade name Lonsurf, code name TAS-102) is a combination drug for the treatment of metastatic colorectal cancer. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. Tipiracil hydrochloride prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.

Trifluridine/tipiracil was approved by the U.S. Food and Drug Administration on September 22, 2015, for use as a third- or fourth-line treatment in metastatic colorectal cancer which has already received both conventional chemotherapy and biologic therapy.

Mechanism of action

File:TAS-102 - Fluridine and Tipiracil Mechanism of Action.png

TAS-102 – trifluridine and tipiracil mechanism of action

TAS-102 consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil. Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Trifluridine (TFT) is incorporated into DNA by phosphorylation by thymidylate kinase (TK) to TF-TMP; TF-TMP then covalently binds to tyrosine 146 of the active site of thymidylate synthase (TS) inhibiting the enzyme's activity. TS is vital to the synthesis of DNA because it is an enzyme involved in the synthesis of the deoxynucleotide, dTTP. Inhibition of TS depletes the cell of dTTP and causes accumulation of dUMP, which increases the likelihood that uracil gets misincorporated into the DNA. Also, subsequent phosphorylations of TF-TMP cause an increased level of TF-TTP within the cell, which results in it being incorporated into DNA. Even though the exact mechanism of how TFT causes DNA damage is not completely understood, it is hypothesized that the incorporation TF-TTP in DNA leads to DNA strand break formation.

In addition to the effects TAS-102 has on DNA synthesis, the thymidine phosphorylase inhibitor (TPI) prevents the degradation of trifluridine via thymidine phosphorylase (TP) when taken orally and also has antiangiogenic properties. Not only has thymidine phosphorylase been shown to be identical to platelet-derived endothelial cell growth factor (PD-ECGF), which is an endogenous factor involved in the formation of new vasculature, but also the products of the enzyme may contribute to the stimulation of endothelial cell chemotaxis.

Physical and chemical properties

TAS-102 has two active pharmaceutical ingredients: a nucleoside analog trifluridine (α,α,α-trifluorothymidine; 5-trifluromethyl-2′-deoxyuridine ; FTD5-trifluoro-2′-deoxythymidine; TFT; CF₃dUrd; FTD; F₃TDR; F₃Thd) and a thymidine phosphorylase inhibitor (TPI), tipiracil hydrochloride(5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride).

The molar concentrations of FTD and TPI in the formulation of TAS-102 is 1.0 to 0.5, respectively.

History

Since the synthesis of 5-fluorouracil (5-FU) in 1957, fluoropyrimidines have been a useful tool in the treatment of many types of cancer. Due to the drawbacks of 5-FU therapy, such as having to be administered over long periods of time via intravenous infusion and the development of resistance in tumors, more convenient and efficacious fluoropyrimidine therapy has been desired. The fluoropyrimidine component of TAS-102, trifluridine, was first synthesized in 1964 by Heidelberger et al. By the late 1960s, Phase I and Phase II clinical trials of intravenous trifluridine alone initially proved to be disappointing. Its pharmacokinetic profile during these clinical trials showed that the drug exhibited a very short half-life while in serum (12 minutes post-injection). In response to its pharmacokinetic properties, adjustments in the dosing regimen demonstrated significant therapeutic benefits in patients with breast cancer and colon cancer; with this new regimen, doses would be given every three hours to total a daily amount of 2.5 mg/kg/day for 8 to 13 days, and as a result, eight out of 23 breast cancer patients were reported to have a therapeutic response while one in six patients with colon cancer showed a near complete response to therapy. Success of trifluridine as an effective anti-cancer agent was short lived, however, due to rapid tumor recurrence upon regression of therapy. Trifluridine therapy in oncology was thus halted.

Researchers later found out that trifluridine, when taken orally, was broken down into the inactive metabolites 5-trifluoromethyluracil and 5-trifluoromethyl-2,4(1H,3,H)-pyrimidinedione (FTY) during its extensive first pass metabolism in the liver via the enzyme thymidine phosphorylase (TP). It was then hypothesized that orally administered FTD concentrations could be increased and maintained if the drug was given with a thymidine phosphorylase inhibitor (TPI).