Tipiracil hydrochloride

Tipiracil is an inhibitor of Thymidine phosphorylase (TP).

Thymidine phosphorylase (TP)is a key enzyme in the pyrimidine nucleoside salvage pathway. It catalyses the reversible phosphorylation of thymidine, and thereby generate thymine and 2-deoxy-D-ribose-1-phosphate.

Tipiracil (TPI) and trifluridine (FTD) are active components of TAS-102 at a molecular ratio of 1:0.5, which is a novel oral nucleoside antitumor agent in clinical trials. Oral administered TPI and FTD co-treatment may differ from that of i.v. administration of FTD alone. [1] When FTD is administered orally, it is rapidly degraded to its inactive form in the intestines and the liver (first-pass effect) [2], but the combination with TPI helps to maintain adequate FTD plasma concentrations [3]. TPI thus, potentiates the antitumor activity of FTD, and the optimal molecular ratio of FTD to TPI has been proven to be 1:0.5. [3]

References:
1. Tsukihara H1, Nakagawa F2, Sakamoto K et al.  Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. Oncol Rep. 2015 May;33(5):2135-42.
2.  Dexter DL, Wolberg WH, Ansfield FJ, Helson L and Heidelberger C: The clinical pharmacology of 5-trifluoro-methyl-2'-deoxyuridine. Cancer Res 32: 247-253, 1972.
3.  Fukushima M, Suzuki N, Emura T et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides. biochem Pharmacol 59: 1227-1236, 2000.

[Antitumor Molecular Mechanism of Trifluridine and Tipiracil Hydrochloride (TAS-102: TFTD)].[Pubmed:26809521]

Gan To Kagaku Ryoho. 2016 Jan;43(1):8-14.

Treatment options for patients with metastatic colorectal cancer (mCRC), who are refractory to standard chemotherapy, are limited. In a global multicenter randomized double-blind phase III study (RECOURSE study), TAS-102 (TFTD) administration significantly improved overall survival rate with favorable safety profile in mCRC patients refractory to standard chemotherapy (HR=0.68, p<0.001). TFTD was approved initially in Japan in March 2014 and is currently under review by health authorities in the United States and Europe. TFTD is expected to play an important role in salvage-line treatment for patients with mCRC. In this review, we present the history of its clinical development and the experimental data that elucidate the underlying molecular mechanism of action of TFTD and its key component, trifluridine.

[Initial Evaluation of the Efficacy and Safety of Tablets Containing Trifluridine and Tipiracil Hydrochloride--Safety Measures Devised by a Multidisciplinary Team Including a Pharmaceutical Outpatient Clinic].[Pubmed:26197742]

Gan To Kagaku Ryoho. 2015 Jul;42(7):817-20.

In May 2014, tablets containing both trifluridine and Tipiracil hydrochloride (Lonsurf(R) tablets) were launched in Japan ahead of other countries, for the treatment of advanced/relapsed unresectable colorectal cancer. The benefits of these tablets in terms of a new therapeutic option have been demonstrated. However, the manufacturer has requested healthcare professionals to help develop safety measures for the appropriate and safe use of the tablets. In this study, we evaluated the efficacy and safety of the tablets in 16 patients who received the tablets at our hospital. Among the 4 evaluable patients, none achieved a complete or partial response. One patient (25.0%) had stable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines outlined in the General Rules of the Study of Colorectal Cancer (The 8th Edition). Lonsurf(R) is considered to be a third-line (or later) treatment. Among the 16 cases studied, Lonsurf(R) was used as a third-, fourth-, and fifth-line treatment in 9, 6, and 1 cases, respectively. Therefore, Grade 3 or worse toxicities were a potential concern. Despite a high incidence of Grade 3 or worse neutropenia (7 of the 16 patients [43.8%]), none of the patients were hospitalized due to neutropenia or other treatment-related adverse events. Pharmacists have made 126 proposals to physicians regarding the use of Lonsurf(R), 121 (96.0%) of which have been adopted. All of the adverse reactions experienced by our patients were resolved after supportive therapy.

Self-Reported Adherence to Trifluridine and Tipiracil Hydrochloride for Metastatic Colorectal Cancer: A Retrospective Cohort Study.[Pubmed:27513940]

Oncology. 2016;91(4):224-230.

BACKGROUND: A novel oral agent that consists of trifluridine and Tipiracil hydrochloride (TFTD) has been established as salvage-line treatment for metastatic colorectal cancer (mCRC). Adherence to TFTD is crucial to maintaining appropriate curative effects. This study sought to clarify adherence to TFTD and identify candidate factors deteriorating adherence at our institution. METHODS: A total of 50 consecutive mCRC patients who received TFTD monotherapy between June 1, 2014 and July 31, 2015 were analyzed in this study. Adherence to TFTD was checked by pharmacists using a self-reported treatment diary and interviewing nonadherents at a pharmaceutical outpatient clinic. The adherence rate was defined as the number of patient intakes per 20 scheduled intakes in one cycle. We retrospectively surveyed the factors from the electronic patient record associated with reduced adherence. We measured relative dose intensity, defined as the dose intensity divided by the initial dose (each in milligrams per square meter per week). RESULTS: Patient characteristics were as follows: males/females, 20/30; median age, 61 years (range, 34-83 years); performance status 0/1, 37/13. Median relative dose intensity of TFTD was 91.0%. Adherence rates were 95.0% for the first cycle of TFTD, 97.3% for the second cycle, 98.0% for the third cycle, and 98.2% for the fourth cycle. Factors associated with deteriorated adherence to TFTD were nausea/vomiting/decreased appetite (27.1%, 23 instances), pain (25.9%, 22 instances), neutropenia (11.8%, 10 instances), and missed dose (4.7%, 4 instances). Increased nonadherence to TFTD was associated with Eastern Cooperative Oncology Group performance status 1, while increased TFTD adherence in the first cycle was associated with prior regimens >/=4. CONCLUSIONS: The high frequency of treatment-related gastrointestinal disorder is the main factor affecting adherence to TFTD. Intensive supportive care in the management of these symptoms could assist adequate adherence to TFTD in mCRC patients.