Trifluridine/tipiracil

Trifluridine/tipiracil, sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed.[3][4] It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor.[3][4] Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.[2]

Trifluridine/tipiracil
Combination of
TrifluridineCytotoxin
TipiracilThymidine phosphorylase inhibitor
Clinical data
Trade namesLonsurf
Other namesTAS-102
AHFS/Drugs.comMonograph
MedlinePlusa615049
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
UNII
KEGG

The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell that fights infection), feeling sick, tiredness and anemia (low red blood cell counts).[2][3][4]

Medical uses

It is used as a third- or fourth-line treatment for metastatic colorectal cancer or gastric cancer, after chemotherapy and biologic therapy.[2][3][4]

Contraindications

The combination caused harm to the fetus of pregnant animals, and it was not tested in pregnant women. Pregnant women should not take it, and women should not become pregnant while taking it.[2]

Adverse effects

The combination severely suppresses bone marrow function, resulting in fewer red blood cells, white blood cells, and platelets, so many people taking it are at risk for infections, anemia, and blood loss from lack of clotting. It also causes digestive problems, with more than 10% of people experiencing loss of appetite, diarrhea, nausea, and vomiting. More than 10% of people experience fatigue and fever.[3][2]

Between 1 and 10% of people have skin and mucosa issues, like rashes and itchiness, or mouth sores, as well as skin sloughing, numbness, redness, and swelling of their palms and soles.[3] Dizziness and confusion are common as well.[3]

Interactions

Only in vitro interaction studies are available. In these, trifluridine used the concentrative nucleoside transporter 1 (CNT1) and equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), and tipiracil was transported by the solute carrier proteins SLC22A2 and SLC47A1. Drugs that interact with these transporters could influence blood plasma concentrations of trifluridine and tipiracil. Trifluridine, being a thymidine phosphorylase inhibitor, could also interact with substrates of this enzyme such as zidovudine.[2]

Pharmacology

Mechanism of action
Mechanism of action. Details see text.

The drug consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil.[2] 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;[5] TF-TMP then covalently binds to tyrosine 146 of the active site of thymidylate synthase (TS) inhibiting the enzyme's activity.[5] TS is vital to the synthesis of DNA because it is an enzyme involved in the synthesis of the deoxynucleotide, thymidine triphosphate (dTTP).[5] Inhibition of TS depletes the cell of dTTP and causes accumulation of deoxyuridine monophosphate (dUMP), which increases the likelihood that uracil gets misincorporated into the DNA.[5] Also, subsequent phosphorylations of TF-TMP cause an increased level of TF-TTP within the cell, which results in it being incorporated into DNA.[5] 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.[5]

Tipiracil prevents the degradation of trifluridine via thymidine phosphorylase (TP) when taken orally and also has antiangiogenic properties.[5][6][7]

History

Since the synthesis of 5-fluorouracil (5-FU) in 1957,[8] fluoropyrimidines have been used to treat many types of cancer.[9] 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.[9] The fluoropyrimidine component of this drug, trifluridine, was first synthesized in 1964 by Heidelberger et al.[9]

By the late 1960s, Phase I and Phase II clinical trials of intravenous trifluridine alone initially proved to be disappointing.[9] Its pharmacokinetic profile during these clinical trials showed that the drug exhibited a very short half-life while in serum (12 minutes post-injection).[9] Adjustments in the dosing regimen improved its effects in small studies, but the effect was short-lived.[9]

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.[6][9] It was then hypothesized that orally administered FTD concentrations could be increased and maintained if the drug was given with a thymidine phosphorylase inhibitor.[9]

Trifluridine/tipiracil was approved by the U.S. FDA in September 2015,[10] and by the European Medicines Agency in April 2016.[11]

References
  1. "Search Page - Drug and Health Product Register". 23 October 2014.
  2. "UK Label: Lonsurf - Summary of Product Characteristics". Electronic Medicines Compendium. August 2017. Retrieved 10 May 2018.
  3. "Lonsurf- trifluridine and tipiracil tablet, film coated". DailyMed. 14 January 2020. Retrieved 20 October 2020.
  4. "Lonsurf EPAR". European Medicines Agency (EMA). Retrieved 20 October 2020.
  5. Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ (June 2007). "Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies". Cancer Science. 98 (6): 779–89. doi:10.1111/j.1349-7006.2007.00477.x. PMID 17441963. S2CID 19183535.
  6. Peters GJ, Bijnsdorp IV (December 2012). "TAS-102: more than an antimetabolite". The Lancet. Oncology. 13 (12): e518-9. doi:10.1016/s1470-2045(12)70426-6. PMID 23182191.
  7. Matsushita S, Nitanda T, Furukawa T, Sumizawa T, Tani A, Nishimoto K, et al. (April 1999). "The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors". Cancer Research. 59 (8): 1911–6. PMID 10213500.
  8. Hoff PM, Cassidy J, Schmoll HJ (1 August 2001). "The evolution of fluoropyrimidine therapy: from intravenous to oral". The Oncologist. 6 Suppl 4 (90004): 3–11. doi:10.1634/theoncologist.6-suppl_4-3. PMID 11585968. S2CID 12355316.
  9. Hong DS, Abbruzzese JL, Bogaard K, Lassere Y, Fukushima M, Mita A, et al. (September 2006). "Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors". Cancer. 107 (6): 1383–90. doi:10.1002/cncr.22125. PMID 16902987. S2CID 32214949.
  10. "FDA approves new oral medication to treat patients with advanced colorectal cancer" (Press release). Silver Spring, MD. U.S. Food and Drug Administration. 2015-09-22. Retrieved 2015-09-23.
  11. "Lonsurf EPAR – Summary for the Public" (PDF). European Medicines Agency. April 2016.
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