U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update:FDA Approves LONSURF (trifluridine and tipiracil)

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FDA Approves LONSURF^® (trifluridine and tipiracil) for the Treatment of Advanced Metastatic Colorectal Cancer

On September 22, 2015, the United States Food and Drug Administration (FDA) approved LONSURF (trifluridine and tipiracil) tablets for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. The approved recommended dosage is 35 mg/m^2 (based on the trifluridine component and rounded to the nearest 5 mg increment) orally twice daily within one hour of completion of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity. Do not exceed 80 mg/dose.

_Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD)_

* /MOA:/ Trifluridine is a thymidine-based nucleoside analogue and tipiracil is a thymidine phosphorylase inhibitor.
* /Dose proportionality:/ The AUC of trifluridine increased more than dose-proportionally over the dose range of 15 (0.43 times the recommended approved dosage) to 35 mg/m^2 . Tipiracil appeared to be dose proportional.
* /Accumulation:/ 3-fold for AUC_0-last and 2-fold for C_max at steady-state for trifluridine. No accumulation was observed for tipiracil.
* /Absorption (tablets):/ The mean relative bioavailability of LONSURF is 100% for trifluridine (T_max [mean]: 2 hours) and 96% for tipiracil (T_max [mean]: 3.5 hours) compared to oral solution. * /Food effect:/ An approximately 40% decrease in trifluridine C_max and tipiracil C_max and AUC was observed following the
administration of LONSURF with a high-fat meal to patients. * /Plasma protein binding:/ Greater than 96% for trifluridine and less than 8% for tipiracil.
* /Terminal half-life (mean):/ 2.1 hours for trifluridine and 2.4 hours for tipiracil at steady state.
* /Metabolism:/ Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite 5-(trifluoromethyl) uracil (FTY).
* /Excretion:/ The mean 48-hour cumulative urinary excretion of unchanged trifluridine and tipiracil was 1.5% and 29.3%, respectively. * /Exposure-safety:/ LONSURF did not have a large effect (i.e. > 20 ms) on the mean QTc interval compared to placebo when administered to cancer patients at the approved recommended dosage.

_Drug Interaction Potential_

* The mean trifluridine AUC_0-last and C_max increased by 37-fold and C_max by 22-fold, respectively, following coadministration of tipiracil and trifluridine as LONSURF compared to trifluridine administered alone.
* Trifluridine, tipiracil, and FTY did not inhibit the CYP enzymes and had no inductive effect on CYP1A2, CYP2B6 or CYP3A4/5 in vitro. * Trifluridine was not an inhibitor of or substrate for human uptake and efflux transporter systems in vitro.

_Use in Specific Populations_

* No dose adjustment to the starting dose of LONSURF is recommended in patients with mild or moderate renal impairment (creatinine clearance (CLcr): 30 to 89 mL/min); however patients with moderate renal impairment may require dose modification for increased toxicity. The estimated mean AUC of trifluridine and tipiracil at steady state was 31% and 34% higher in patients with mild renal impairment (CLcr = 60-89 mL/min) and 43% and 65% higher in patients with moderate renal impairment (CLcr: 30 to 59 mL/min) based upon a pop-PK analysis of a Phase 3 trial. In addition, patients with moderate renal impairment had a higher incidence of Grade 3 or higher adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr greater than or equal to 90 mL/min) or patients with mild renal impairment (CLcr: 60 to 89 mL/min) in this trial. The effect of severe renal impairment or end-stage renal disease (CLcr less than 30 mL/min) on trifluridine and tipiracil exposure is unknown. * The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of
trifluridine or tipiracil: age, sex, race (White or Asian), or mild hepatic impairment. The effect of moderate to severe hepatic impairment on trifluridine and tipiracil exposure is unknown.

_Safety and Efficacy_

The clinical efficacy and safety of LONSURF were evaluated in an international, randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS). A statistically significant median 1.8 month improvement in overall survival (Hazard ratio [95% CI]: 0.68 (0.58, 0.81) p <0.001) was demonstrated in patients in the LONSURF plus best supportive care (BSC) arm compared to those who received placebo plus BSC. The most common adverse reactions reported in this trial were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

Full prescribing information is available at http://go.usa.gov

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/This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA./