title: A phase 1 study of the pharmacokinetics of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (components of TAS-102) vs trifluridine alone.
abstract: Background Trifluridine, a thymidine-based chemotherapeutic, has limited bioavailability after clinical administration as it is rapidly degraded via thymidine phosphorylase. An oral combination tablet combines trifluridine with a potent thymidine phosphorylase inhibitor, tipiracil hydrochloride. This study's objective was to evaluate whether trifluridine/tipiracil (TAS-102) administration increases trifluridine exposure vs trifluridine alone. Methods This open-label pharmacokinetic study randomly assigned patients with advanced solid tumors into two groups. On the morning of day 1, one group received a single 35 mg/m2dose of trifluridine/tipiracil and the other group received a single 35-mg/m2dose of trifluridine. Both groups received trifluridine/tipiracil 35 mg/m2on the evening of day 1, then twice daily on days 2-5 and 8-12 in a 28-day cycle. Results Twenty patients received an initial one-time dose of trifluridine alone and 19 other patients received an initial dose of trifluridine/tipiracil. Trifluridine area under the curve (AUC0-last) and maximum observed plasma concentrations (Cmax) were approximately 37- and 22-fold higher, respectively, with trifluridine/tipiracil vs trifluridine alone. Plasma concentrations of the major metabolite of trifluridine were lower following the administration of trifluridine/tipiracil vs trifluridine alone. Conclusion Tipiracil administered in combination with trifluridine significantly increased exposure to trifluridine compared with trifluridine alone.
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.affiliation: University of California, Los Angeles, 2020 Santa Monica Blvd., Ste. 600, Santa Monica, CA, 90404, USA.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.affiliation: Taiho Oncology, Inc., 101 Carnegie Center, Suite 101, Princeton, NJ, 08540, USA.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: South Texas Accelerated Research Therapeutics, 4319 Medical Dr., Ste. 205, San Antonio, TX, 78229, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: Rasco
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: University of Pittsburgh Cancer Institute/UPMC, 5150 Centre Avenue, Fifth Floor, Pittsburgh, PA, 15232, USA. sunw@upmc.edu.
authors.forename: Weijing
authors.initials: W
authors.lastname: Sun
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013941:Thymine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D014271:Trifluridine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; C000613754:tipiracil; D013941:Thymine; D014271:Trifluridine
keywords: Advanced solid tumors; Fluoropyrimidine; Pharmacokinetics; Trifluridine; Trifluridine/tipiracil