Drug Monographs: Trabectedin and Trifluridine-Tipiracil

Abstract

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases.

Drug name: Trabectedin

Synonyms: Yondelis; Ecteinascidin-743; ET-743

Mechanism of Action

Trabectedin is a tetrahydroisoquinolone alkaloid that binds to N2 amino groups of guanine in the DNA minor groove, with a portion of the molecule protruding and interacting with proteins such as transcription factors and DNA repair proteins. In low concentrations, trabectedin inhibits in vitro production of CCL2 and interleukin-6, inhibiting macrocyte recruitment at the tumor and tumor growth. ¹

Pharmacokinetics

For a 24-hour infusion of 0.9 mg/m² to 1.5 mg/m², the mean time to maximum concentration (T_max) is 16.5 hours to 17.2 hours; the maximum concentration (C_max) was 652 pg/mL to 2,070 pg/mL; the half-life (T_½) is 124 to 221 hours; the 1 hour, 48 hour, and overall area under the time versus concentration curve (AUC) is 46.9 to 96.3 ng•h/mL, 33.3 to 52.4 ng•h/mL, and 74.9 to 132 ng•h/mL, respectively. The steady state volume of distribution (V_{d ss}) is 2,030 to 2,470 L/m² and 3,380 to 3,800 L. Clearance is 11.6 to 18.7 L/h/m² and 21 to 31.4 L/h. ²

For 1.5 mg/m² given over 24 hours, the mean AUC is 40.0 ng•h/mL, the mean clearance is 35.6 L/h/m², and mean C_max is 1.04 ng/mL. ³ The manufacturer reports the protein binding is 97%. The V_{d ss} is greater than 5,000 L; clearance is 31.5 L/h; T_½ is 175 hours. The drug is metabolized in the liver, primarily by CYP3A. Following a 3-hour or 24-hour infusion, 64% of the drug is excreted within 24 days, with 58% excreted in the feces and 6% in the urine. ⁴

Doses of 0.46 to 0.7 mg/m² given as a 1-hour infusion have a C_max of 3.91 ng/mL to 16.6 ng/mL, AUC of 7.78 ng•h/mL to 72.6 ng•h/mL, clearance of 49.3 L/h to 135.8 L/h, a V_{d ss} of 1,434 L to 3,025 L, and a T_½ of 17.2 hours to 100.1 hours. ⁵

Doses of 0.3 to 0.65 mg/m² given as a 3-hour infusion are reported to have a C_max of 0.72 ng/mL to 4.87 ng/mL, AUC of 4.94 ng•h/mL to 20.05 ng•h/mL, clearance of 51.9 L/h to 102.3 L/h, a V_{d ss} of 2,658 L to 3,704 L, and a T_½ of 39.5 hours to 64.6 hours. ⁵

In pediatric patients given 1.1 mg/m² over 24 hours, the T_½ was 94.8 hours; the 8 hour and overall AUC were 23.5 ng•h/mL and 28.8 ng•h/mL, respectively. The V_{d ss} was 3,010 L/m². Clearance was 38 L/h/m². For 1.5 mg/m² over 24 hours, the T_½ was 83.2 to 104.3 hours; the 8 hour and overall AUC were 29.3 to 48.9 ng•h/mL and 28.8 to 60.4 ng•h/mL, respectively. The V_{d ss} was 1,880 to 4,020 L/m². Clearance was 24.8 to 40.5 L/h/m². ⁶

For 1.3 mg/m² given as a 3-hour infusion, the mean C_max is 3.98 to 6.1 ng/mL; the T_max is 2.8 to 2.9 hours, the 48 hour and overall AUC are 17 to 31.6 ng•h/mL and 32.6 ng•h/mL, respectively. The V_d is 5,462 L, and the clearance is 20.3 to 39.6 L/h. ⁷

No significant differences in pharmacokinetics or antitumor activity in patients with mild to severe hepatic dysfunction given 0.75 to 1.3 mg/m² as a 3-hour infusion. ⁸

Selected therapeutic regimens of trabectedin appear in Table 1 .

Table 1.

Selected therapeutic regimens of trabectedin

Daily dose	Route of administration	Administered on day(s)	Cycle length	Total dose/cycle	References
1–hour infusion
0.46 to 0.8 mg/m2	IV	1	3 weeks	0.46 to 0.8 mg/m2	5
3-hour infusion
0.3 to 0.65 mg/m2	IV	1	3 weeks	0.3 to 0.65 mg/m2	5
0.58 mg/m2	IV	1	3 weeks	0.58 mg/m2	9 - 11
0.58 mg/m2	IV	1	3 or 4 weeks	0.58 mg/m2	1
0.58 mg/m2	IV	1, 8, 15	3 weeks	1.74 mg/m2	13
0.75 mg/m2	IV	1	3 weeks	0.75 mg/m2	8
0.9 mg/m2	IV	1	3 weeks	0.9 mg/m2	8
1.1 mg/m2	IV	1	3 weeks	1.1 mg/m2	6, 8, 14
1.3 mg/m2	IV	1	3 weeks	1.3 mg/m2	7, 10, 12, 14–20
1.65 mg/m2	IV	1	3 weeks	1.65 mg/m2	6, 14, 19
24–hour infusion
0.9 mg/m2	CIVI	1	3 weeks	0.9 mg/m2	2
0.9 to 1.5 mg/m2	CIVI	1	3 weeks	0.9 to 1.5 mg/m2 1.1 mg/m2	22
1.1 mg/m2	CIVI	1	3 weeks	1.1 mg/m2	6, 23
1.2 mg/m2	CIVI	1	3 weeks	1.2 mg/m2	2, 11, 24
1.3 mg/m2	CIVI	1	3 weeks	1.3 mg/m2	23, 25
1.5 mg/m2 a	CIVI	1	3 weeks	1.5 mg/m2	2–4, 6, 9–11, 16, 19, 21, 23, 25–37
1.7 mg/m2	CIVI	1	3 weeks	1.7 mg/m2	6

Note: CIVI = 24-hour continuous infusion; IV = intravenous.

^aConforms to dosing information listed in the manufacturer's labeling.

Preparation

• 1.Follow institutional policies for preparation of hazardous medications when preparing trabectedin.
• 2.Use trabectedin powder for injection.
• 3.Reconstitute the drug to a concentration of 0.5 mg/mL with sterile water for injection.
• 4.Dilute in 500 mL 0.9% sodium chloride (NS) or 5% dextrose in water (D5W).

Stability

Reconstituted vials and solutions for infusion are stable for 30 hours from reconstitution of the vial.

Administration

• 1.Trabectedin is administered as a 1-hour, ⁵ 3-hour,^1,5–21 or 24-hour infusion.^{2–4,6,9–11,16,19,21–37}
• 2.The manufacturer recommends infusion through a 0.2 micron polyethersulfone filter “to reduce the risk of exposure to adventitious pathogens that may be introduced during solution preparation.” ⁴
• 3.If the solution is prepared by a competent pharmacist or technician, using accepted standards of practice in conformance with USP Chapter <797>, use of an inline filter is unnecessary.

Toxicities

Most of the toxicities listed below are presented according to their degree of severity. Higher grades represent more severe toxicities. Although there are several grading systems for cancer chemotherapy toxicities, all are similar. One of the frequently used systems is the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). Oncologists generally do not adjust doses or change therapy for grade 1 or 2 toxicities, but make, or consider, dosage reductions or therapy changes for grade 3 or 4 toxicities. Incidence values are rounded to the nearest whole percent unless incidence was less than or equal to 0.5%.

1.3 mg/m² – 3-hour infusion

• A.Cardiovascular: Deep venous thrombosis (grade 3 or 4) 5% ¹⁴ ; dehydration (grade 3 or 4) 4% ²¹ ; phlebitis (grade 1) 2%, ¹⁶ (grade 1 or 2) 11%, ¹⁸ (grade 2) 11%, ¹⁶ (grade 3 or 4) 6% ¹⁸ ; unspecified “cardiac disorders” (grade 3 or 4) 7%. ²²
• B.Central Nervous System: Headache 44%. ¹²
• C.Constitutional: Asthenia 50% to 56%,^12,17 (grade 1) 27%, ¹⁵ (grade 2) 6% to 44%,^15,16 (grade 3) 2% to 14%,^15–17 (grade 3 or 4) 13%, ⁷ (grade 4) 2%^16,17; fatigue 34% to 44%,^12,17 (grade 1) 15%, ¹⁶ (grade 1 or 2) 39% to 57%,^10,14,18,20 (grade 2) 23%, ¹⁶ (grade 3) 7% to 13%,^{10,16,17,19,20} (grade 3 or 4) 2% to 20%,^12,14,18,22 (grade 4) 0.4% to 2%^10,16; fever (grade 1) 8%, ¹⁵ (grade 1 or 2) 38%, ¹⁴ (grade 3) 2%, ¹⁶ (grade 3 or 4) 28%. ¹²
• D.Dermatologic: Alopecia (grade 1) 8%, ¹⁶ (grade 2) 2%. ¹⁶
• E.Endocrine/Metabolic: Increased creatine phosphokinase (CPK) (grade 1 or 2) 26%, ²⁰ (grade 3) 6%, ²⁰ (grade 4) 3% to 4%^17,20; hyperglycemia (grade 3) 2% ¹⁷ ; hyperkalemia (grade 3) 2% ¹⁷ ; hypoglycemia (grade 4) 2% ¹⁷ ; hypokalemia (grade 3) 4% ¹⁷ ; hyponatremia (grade 3) 6%, ¹⁷ (grade 3 or 4) 4%. ²²
• F.Gastrointestinal: Anorexia (grade 1) 11%, ¹⁶ (grade 1 or 2) 18% to 57%,^14,20 (grade 2) 6% ¹⁶ ; constipation 48%, ¹² (grade 1) 11%, ¹⁶ (grade 1 or 2) 10% to 26%,^14,19 (grade 2) 13%, ¹⁶ (grade 3) 2% to 5%^16,19; diarrhea (grade 1) 8%, ¹⁶ (grade 1 or 2) 14%, ¹⁴ (grade 2) 2% ¹⁶ ; dysgeusia (grade 1) 6%, ¹⁶ (grade 2) 2% ¹⁶ ; dyspepsia (grade 1 or 2) 10% ¹⁴ ; nausea 56% to 62%,^12,17 (grade 1) 30%, ¹⁶ (grade 1 or 2) 39% to 62%,^10,14,18,20 (grade 2) 32%, ¹⁶ (grade 3) 3% to 13%,^10,16,18,19 (grade 3 or 4) 5% to 7%,^14,21 (grade 4) 13% ¹⁹ ; nausea and vomiting (grade 1) 39%, ¹⁵ (grade 2) 34%, ¹⁵ (grade 3) 5% ¹⁵ ; stomatitis (grade 1) 8%, ¹⁶ (grade 1 or 2) 14%, ¹⁴ (grade 2) 4% ¹⁶ ; vomiting 20% to 42%,^12,17 (grade 1) 19%, ¹⁶ (grade 1 or 2) 16% to 62%,^10,14,18,20 (grade 2) 21%, ¹⁶ (grade 3) 4% to 9%,^10,16 (grade 3 or 4) 6% to 13%,^7,14,18,21 (grade 4) 0.4% ¹⁰ ; weight loss (grade 1 or 2) 13%. ²⁰
• G.Hematologic: Anemia (grade 1 or 2) 72% to 81%,^14,18,20 (grade 3) 5% to 6%,^17,20 (grade 3 or 4) 9% to 17%,^7,14,18,21 (grade 4) 5% to 13%^19,20; febrile neutropenia (grade 3) 5%, ²⁰ (grade 3 or 4) 13% to 25%,^7,14,21 (grade 3 or 4) 5% ²⁰ ; leukopenia (grade 1 or 2) 33% to 42%,^18,20 (grade 3) 13% to 34%,^7,19,20 (grade 3 or 4) 1% to 33%,^12,18,21 (grade 4) 11% ²⁰ ; lymphopenia (grade 1 or 2) 34% to 44%,^18,20 (grade 3) 38% to 45%,^19,20 (grade 3 or 4) 13% to 28%,^18,22 (grade 4) 8% ²⁰ ; neutropenia 34% to 40%,^12,17 (grade 1) 17%, ¹⁵ (grade 1 or 2) 11% to 47%,^10,14,18,20 (grade 2) 27%, ¹⁵ (grade 3) 8% to 37%,^{10,15,17,19,20} (grade 3 or 4) 6% to 46%,^{7,12,14,17,18,21} (grade 4) 4% to 41%^10,15,17,20; thrombocytopenia (grade 1) 20%, ¹⁵ (grade 1 or 2) 24% to 33%,^10,12,18,20 (grade 2) 3%, ¹⁵ (grade 3) 5% to 13%,^10,15,17,20 (grade 3 or 4) 2% to 40%,^{7,12,14,18,21} (grade 4) 3% to 11%.^10,15,20
• H.Hepatic: “Abnormal hepatic function” (grade 3 or 4) 25% to 40%^7,12; increased alanine aminotransferase (ALT) 40% to 68%,^12,17 (grade 1 or 2) 29% to 53%,^10,12,18,20 (grade 3) 6% to 51%,^10,17,19 (grade 3 or 4) 15% to 67%,^{12,14,18,20,21} (grade 4) 2% to 17%^{10,15,17,19,20}; increased alkaline phosphatase (AP) 36% to 44%,^12,17 (grade 1 or 2) 38% to 91%,^10,14,20 (grade 3) 2% to 3%,^10,20 (grade 3 or 4) 10%, ¹⁴ (grade 4) 0.4% ¹⁰ ; increased aspartate aminotransferase (AST) 40%, ¹² (grade 1 or 2) 43% to 66%,^10,14,20 (grade 3) 18% to 44%,^10,17,19,20 (grade 3 or 4) 3% to 57%,^12,14,21 (grade 4) 2% to 5%^10,17; increased bilirubin (grade 1 or 2) 12% to 68%,^10,14,15,20 (grade 3) 2% to 13%,^10,17,19,20 (grade 3 or 4) 5% ¹⁴ ; increased gamma-glutamyl transferase (GGT) (grade 3 or 4) 2% to 39%^12,21; unspecified hepatotoxicity (grade 3) 2%. ¹⁴
• I.Hypersensitivity: Injection site reactions (grade 1) 6%, ¹⁶ (grade 2) 2%, ¹⁶ (grade 3) 2%. ¹⁶
• J.Infection: Cellulitis (grade 1 or 2) 6%, ¹⁸ (grade 3 or 4) 6% ¹⁸ ; unspecified (grade 3 or 4) 5% to 13%.^14,21
• K.Musculoskeletal: Myalgia (grade 1) 4%, ¹⁶ (grade 1 or 2) 29%, ¹⁴ (grade 2) 4%, ¹⁶ (grade 3 or 4) 5%. ¹⁴
• L.Neurologic: Paresthesia (grade 1) 8%, ¹⁶ (grade 1 or 2) 13% ²⁰ ; peripheral sensory neuropathy (grade 1) 4%, ¹⁶ (grade 2) 6%. ¹⁶
• M.Pain: Abdominal 40%, ¹² (grade 1) 4%, ¹⁶ (grade 1 or 2) 11% ²⁰ ; skeletal 20%, ¹² (grade 3) 6%. ¹⁷
• N.Pulmonary: Dyspnea 28%, ¹² (grade 1 or 2) 8%, ²⁰ (grade 2) 9%, ¹⁶ (grade 3) 3% to 4%,^17,20 (grade 3 or 4) 9%, ²¹ (grade 4) 2%. ¹⁶
• O.Renal: “Abnormal renal function” (grade 3) 6%, ¹⁷ (grade 4) 2% ¹⁶ ; increased creatinine (grade 3) 4% ¹⁷ ; unspecified “renal and urinary disorders” (grade 3 or 4) 7%. ²¹

1.5 mg/m² – 24-hour infusion

• A.Cardiovascular: Arrhythmia (grade 3 or 4) 5% ³⁷ ; heart failure (grade 3 or4) 4% ³⁷ ; myocardial infarction (grade 4) 20% ¹¹ ; phlebitis (grade 1) 2%, ¹⁶ (grade 2) 6%, ¹⁶ (grade 3) 2% ¹⁶ ; pulmonary edema (grade 3) 20% ¹¹ ; pulmonary emboli (grade 4) 5% ³⁷ ; unspecified (grade 1 or 2) 2%, ³⁶ (grade 3) 5% ³³ ; venous thrombosis (grade 3) 20%, ¹¹ (grade 3 or 4) 4%. ³⁷
• B.Central Nervous System: Headache (grade 1) 4%, ²⁶ (grade 1 or 2) 13%, ³⁵ (grade 2) 4%, ²⁶ (grade 3) 1% to 7%.^26,36
• C.Constitutional: Asthenia 80%, ²⁷ (grade 2) 2% ¹⁶ ; fatigue (grade 1) 10% to 40%,^{16,28,30,33,34} (grade 1 or 2) 35% to 59%,^{10,11,32,35,36} (grade 2) 7% to 44%,^{16,28,30,33,34} (grade 3) 5% to 20%,^{10,11,16,28,30,34,36} (grade 3 or 4) 4% to 17%,^{11,21,27,32,35,37} (grade 4) <1% to 4%^{10,28,30,34,36}; fever (grade 1) 4% to 7%,^16,26 (grade 1 or 2) 7%, ³⁵ (grade 2) 2% to 4%^16,26; flu-like syndrome (grade 2) 5% ³³ ; lethargy (grade 1) 26%, ²⁶ (grade 2) 41%, ²⁶ (grade 3) 7% ²⁶ ; unspecified (grade 1) 15%. ³³
• D.Dermatologic: Alopecia 4%, ²⁷ (grade 1) 7%, ¹⁶ (grade 1 or 2) 2%,^35,36 (grade 4) 1% ³⁶ ; unspecified reactions (grade 1) 20%, ³³ (grade 2) 10%. ³³
• E.Endocrine/Metabolic: Increased CPK (grade 1) 17%, ²⁸ (grade 1 or 2) 25% to 36%,^32,35,36 (grade 2) 6%, ²⁸ (grade 3) 3%,^28,36 (grade 3 or 4) 4% to 9%,^32,35 (grade 4) 2% ³⁶ ; unspecified metabolic reactions (grade 1) 25%, ³³ (grade 2) 20%, ³³ (grade 3) 15%. ³³
• E.Gastrointestinal: Anorexia 20%, ²⁷ (grade 1) 9% to 22%,^16,26 (grade 1 or 2) 23% to 30%,^11,35 (grade 2) 4% to 7%,^16,26 (grade 3) 1% to 2%,^16,26 (grade 3 or 4) 2%^27,35; constipation (grade 1) 8% to 13%,^16,34 (grade 1 or 2) 14% to 20%,^11,32,35 (grade 2) 3% to 11%,^16,34 (grade 3) 1% to 2%,^16,34 (grade 3 or 4) 3%, ³² (grade 4) <1% ³⁴ ; diarrhea 6%, ²⁷ (grade 1) 2% to 22%,^16,26,30 (grade 1 or 2) 16%, ³⁵ (grade 2) 4%,^16,26 (grade 3) 4% to 20%^11,26; dysgeusia (grade 1) 2%, ¹⁶ (grade 1 or 2) 7%, ³⁵ (grade 2) 6% ¹⁶ ; increased lipase (grade 3) 20% ¹¹ ; intestinal occlusion (grade 3 or 4) 4%, ³⁷ nausea 80%, ²⁷ (grade 1) 16% to 55%,^{16,26,28,33,34} (grade 1 or 2) 55% to 69%,^{10,11,32,35,36} (grade 2) 6% to 52%,^{16,26,28,33,34} (grade 3) 3% to 14%,^{10,16,26,28,29,34,36} (grade 3 or 4) 2% to 12%,^21,27,32,35 (grade 4) 0.2% ¹⁰ ; nausea or vomiting (grade 3 or 4) 9% to 13% ³¹ ; stomatitis 9%, ²⁷ (grade 1) 4% to 7%,^16,26,30 (grade 1 or 2) 2% to 5%,^35,36 (grade 2) 2% to 15%,^16,26 (grade 3 or 4) 2% ³⁵ ; vomiting 59%, ²⁷ (grade 1) 8% to 50%,^{16,26,28,30,33,34} (grade 1 or 2) 21% to 43%,^{10,11,32,35,36} (grade 2) 1% to 24%,^{16,26,28,30,33,34} (grade 3) 1% to 20%,^{10,11,16,26,28,30,34,36} (grade 3 or 4) 2% to 10%,^{11,21,27,29,32,35} (grade 4) 0.5% to 4%^10,30,34; weight loss (grade 1 or 2) 5%, ³⁵ (grade 3 or 4) 2%. ³⁵
• F.Hematologic: Anemia 76%, ²⁷ (grade 1) 4% to 59%,^26,30,33,34 (grade 1 or 2) 75% to 89%,^32,35,36 (grade 2) 7% to 52%,^{26,28,30,33,34} (grade 3) 4% to 5%,^26,33,34,36 (grade 3 or 4) 3% to 22%,^{21,27,29,31,32,35} (grade 4) 1% to 7%^26,28,34,36; coagulopathies (grade 1) 5%, ³³ febrile neutropenia (grade 3) 7% to 20%,^11,26 (grade 3 or 4) 2% to 9%,^27,29,35 (grade 4) 1% ³⁶ ; hemorrhage (grade 1 10%, ³³ leukopenia 85%, ²⁷ (grade 1) 33%, ²⁶ (grade 1 or 2) 49% to 55%,^11,32,35 (grade 2) 30% to 35%,^26,28,33 (grade 3) 15% to 50%,^26,28,33 (grade 3 or 4) 24% to 46%,^{11,21,27,29,32,35} (grade 4) 3% to 7%^26,28,33; lymphopenia (grade 1 or 2) 35% to 48%,^11,32 (grade 3 or 4) 12% to 40%^11,21,32; neutropenia 81%, ²⁷ (grade 1) 3% to 15%,^26,30,34 (grade 1 or 2) 25% to 41%,^{10,11,32,35,36} (grade 2) 6% to 22%,^{26,28,30,33,34} (grade 3) 8% to 55%,^{10,26,28,30,33,34,36} (grade 3 or 4) 9% to 61%,^{11,21,27,29,31,32,34,37} (grade 4) 8% to 33%^{10,26,28,30,34,36}; thrombocytopenia 37%, ²⁷ (grade 1) 3% to 20%,^26,30,33,34 (grade 1 or 2) 25% to 43%,^{10,11,32,35,36} (grade 2) 2% to 11%,^26,30,34 (grade 3) 4% to 15%,^{10,11,33,34,36} (grade 3 or 4) 5% to 19%,^{11,21,27,29,31,32,35,37} (grade 4) 2% to 6%.^{10,26,30,34,36,37}
• G.Hepatic: Increased ALT 100%, ²⁷ (grade 1) 4% to 41%,^26,28,30,34 (grade 1 or 2) 40% to 69%,^{10,11,32,35,36} (grade 2) 4% to 33%,^26,28,30,34 (grade 3) 10% to 56%,^{10,26,28,30,34,36} (grade 3 or 4) 7% to 53%,^{27,29,31,32,35,37} (grade 4) 1% to 15%^{10,26,28,30,34,36,37}; increased AP 65%,27 (grade 1) 5% to 67%,^{26,28,30,33,34} (grade 1 or 2) 40% to 57%,^10,11,35,36 (grade 2) 4% to 22%,^28,30,34 (≥grade 2) 18%, ²⁹ (grade 3) 1% to 3%,^10,34,36 (grade 3 or 4) 5% to 22%,^11,21,35 (grade 4) 0.4% to <1%^10,34; increased AST 98%, ²⁷ (grade 1) 4% to 31%,^{26,28,30,33,34} (grade 1 or 2) 38% to 62%,^{10,11,32,35,36} (grade 2) 3% to 28%,^{26,28,30,33,34} (grade 3) 4% to 62%,^{10,26,28,30–34,36,37} (grade 3 or 4) 20% to 57%,^{11,21,27,29,35} (grade 4) 1% to 30%^{10,26,28,30,34,37}; increased bilirubin 37%, ²⁷ (grade 1) 5% to 18%,^26,28,33 (grade 1 or 2) 17% to 23%,^10,32,35,36 (grade 2) 7%, ³⁰ (≥grade 2) 18%, ²⁹ (grade 3) 1% to 4%,^10,30,36 (grade 3 or 4) 2% to 7%,^32.35 (grade 4) 7% ²⁶ ; increased GGT (grade 1) 7%, ³⁰ (grade 1 or 2) 55% to 75%,^11,32 (grade 2) 30%, ³⁰ (grade 3) 44%, ³⁰ (grade 3 or 4) 2% to 49%,^11,21,31,32 (grade 4) 4% ³⁰ ; unspecified hepatotoxicity (grade 2) 2%, ¹⁶ (grade 3) 7%. ¹⁶
• H.Hypersensitivity: Injection site reactions (grade 1) 6%, ¹⁶ (grade 2) 6%, ¹⁶ (grade 3) 2% ¹⁶ ; unspecified allergy 2%, ²⁷ (grade 1) 7%. ²⁶
• I.Infection: Pneumonia (grade 3 or 4) 4% ³⁷ ; unspecified 4%, ²⁷ (grade 2) 10% to 11%,^26,33 (grade 3) 5%, ³³ (grade 3 or 4) 7% to 10%.^21,26
• J.Musculoskeletal: Myalgia (grade 1) 2% to 11%,^16,26 (grade 2) 2% ¹⁶ ; unspecified (grade 1) 20%, ³³ (grade 2) 5%. ³³
• K.Neurologic: Paresthesia (grade 1) 9% ¹⁶ ; peripheral sensory neuropathy (grade 1) 4% to 10%,^16,33 (grade 2) 2% ¹⁶ ; unspecified (grade 1) 20%. ³³
• L.Ocular: Unspecified (grade 1) 15%, ³³ (grade 2) 5%. ³³
• M.Pain: Abdominal (grade 1) 2%, ¹⁶ (grade 1 or 2) 10%, ³⁵ (grade 2) 4% to 7%,^16,26 (grade 3) 2% to 4%,^16,26 (grade 3 or 4) 2% ³⁵ ; unspecified (grade 1) 50%, ³³ (grade 2) 10%, ³³ (grade 3 or4) 5%. ³⁷
• N.Pulmonary: Dyspnea (grade 3) 2% to 20%,^11,16 (grade 3 or 4) 2% ²¹ ; unspecified reaction (grade 1) 20%, ³³ (grade 2) 5%. ³³
• O.Renal: Increased creatinine (grade 1) 18%, ²⁶ (grade 1 or 2) 17% to 35%,^32,35,36 (≥grade 2) 13%, ²⁹ (grade 3 or 4) 3% to 5%,^32,35 (grade 4) 2% ³⁶ ; unspecified (grade 1) 5%. ³³

Dose Adjustment

• A.
  Hepatic

  • 1.
    Bilirubin greater than the upper limit of normal (ULN), delay therapy up to 3 weeks and reduce dose 20%. ⁴
  • 2.
    ALT or AST

    • (a)
      Greater than 2.5 times the ULN, delay therapy for up to 3 weeks. ⁴
    • (b)
      Greater than 5 time the ULN, reduce dose 20%. ⁴
• B.Renal: No information available. ⁴

Drug name: Trifluridine-Tipiracil

Synonyms: Lonsurf; TAS-102

Comment

Trifluridine-tipiracil is a combination of 2 agents that have complementary mechanisms of action.

Mechanism of Action

Trifluridine is a pyrimidine antimetabolite that inhibits DNA synthesis by impeding the activity of thymidylate synthetase.^38–40 Trifluridine is also incorporated into DNA, resulting in single strand breaks. ⁴¹ Tipiracil is a thymidine phosphoralase inhibitor that has some intrinsic antiangiogenic activity, ⁴² but also enhances the bioavailability of trifluridine by inhibiting its metabolism in the liver and intestines by thymidine phosphorylase.^43,44

Pharmacokinetics

In doses of 50 to 100 mg/m²/day given orally, on day 1 trifluridine has a mean C_max of 8,140 to 13,050 ng/mL and a mean T_max of 0.5 to 0.75 hours. The 24-hour AUC is 15,938 to 27,118 ng•h/mL, and V_d is 0.174 to 0.187 L/kg. The clearance is 0.0763 to 0.0985 L/h/kg, with a T_½ of 1.37 to 1.57 hours. In 24 hours, 1% to 5.7% of a dose is excreted in the urine. ⁴⁴

On day 14, the C_max is 8,938 to 12,500 ng/mL, and the T_max is 0.85 to 1.33 hours. The 24-hour AUC is 30,248 to 73,874 ng•h/mL, and V_d is 0.0719 to 0.117 L/kg. The clearance is 0.0303 to 0.0424 L/h/kg, with a T_½ of 1.55 to 2.51 hours. By day 14, 9.3% to 16.7% is excreted in the urine. ⁴⁴

In doses of 50 to 100 mg/m²/day given orally, on day 1 trifluridine has a mean C_max of 212 to 246 ng/mL and a mean T_max of 1.55 to 2.0 hours. The 24-hour AUC is 774 to 1,075 ng•h/mL, and V_d is 3.1 to 11.8 L/kg. The clearance is 0.786 to 1.14 L/h/kg, with a T_½ of 3.05 to 6.68 hours. In 24 hours, 2.46% to 50.4% of a dose is excreted in the urine. ⁴⁴

On day 14, the C_max is 167 to 223 ng/mL, and the T_max is 1.75 to 2.0 hours. The 24-hour AUC is 661 to 719 ng•h/mL, and V_d is 3.46 to 9.53 L/kg. The clearance is 0.884 to 1.6 L/h/kg, with a T_½ of 1.5 to 7.46 hours. By day 14, 10.2 % to 24.8 % is excreted in the urine. ⁴⁴

Following administration of 35 mg/m² twice daily, the mean t_1/2 of trifluridine was 1.4 hours and of tipiracil was 2.1 hours following a single dose. At steady state, the mean elimination t_1/2 of trifluridine was 2.1 hours and of tipiracil was 2.4 hours. Following a single oral administration of 35 mg/m², the mean T_max of trifluridine was around 2 hours.

Trifluridine is highly (>96%) protein bound; while tipiracil binding is less than 8%.

Trifluridine metabolized by thymidine phosphorylase to 5-(trifluoromethyl) uracil (FTY) and inactive metabolite. Following a single 60-mg dose, the mean 48-hour cumulative urinary excretion was 1.5% for unchanged trifluridine, 19.2% for FTY, and 29.3% for unchanged tipiracil. ⁴⁵

Selected therapeutic regimens of trifluridine-tipiracil appear in Table 2 .

Table 2.

Selected therapeutic regimens of trifluridine-tipiracil

Daily dose (based on trifluridine)	Route of administration	Administered on day(s)	Cycle length	Total dose/cycle	References
25 mg/m2 twice daily		1,2,3,4,5	28 days	500 mg/m2	50
	PO	8,9,10,11,12
30 mg/m2 twice daily		1,2,3,4,5	28 days	600 mg/m2	47
	PO	8,9,10,11,12
35 mg/m2 twice daily a		1,2,3,4,5	28 days	700 mg/m2	45, 47- 49
	PO	8,9,10,11,12
40 mg/m2 twice daily		1,2,3,4,5	28 days	800 mg/m2	50
	PO	8,9,10,11,12
60 mg/m2 daily b		1,2,3,4,5	28 days	600 mg/m2	46, 51
	PO	8,9,10,11,12
70 mg/m2 daily b		1,2,3,4,5	28 days	700 mg/m2	46, 51
	PO	8,9,10,11,12
80 mg/m2 daily b		1,2,3,4,5	28 days	800 mg/m2	51
	PO	8,9,10,11,12
100 mg/m2	PO	1 through 14	28 days	1,400 mg/m2	44

Note: PO = oral.

^aConforms to dosing information listed in the manufacturer's labeling.

^bGiven in divided doses 3 times a day.

Preparation

Trifluridine-tipiracil is available as tablets containing:

• A.15 mg/6.14 mg of trifluridine and tipiracil, respectively
• B.20 mg/8.19 mg of trifluridine and tipiracil, respectively

Stability

• A.Trifluridine-tipiracil should be stored at 20°C to 25°C (68°F to 77°F).
• B.Brief (less than 24 hours) exposure to temperatures up to 30°C (86°F) is acceptable.

Administration

• A.Trifluridine-tipiracil is administered orally, twice a day.
• B.The medication should be taken within 1 hour of eating.
• C.Doses are based on the trifluridine content and should be rounded to the nearest 5 mg.

Toxicities

Most of the toxicities listed below are presented according to their degree of severity. Higher grades represent more severe toxicities. Although there are several grading systems for cancer chemotherapy toxicities, all are similar. One of the frequently used systems is the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). Oncologists generally do not adjust doses or change therapy for grade 1 or 2 toxicities; but make, or consider, dosage reductions or therapy changes for grade 3 or 4 toxicities. Incidence values are rounded to the nearest whole percent unless incidence was less than or equal to 0.5%.

• A.Cardiovascular: Cardiac ischemia (grade 3 or 4) <1%. ⁴⁶
• B.Constitutional: Asthenia 18%, ⁴⁶ (grade 3 or 4) 3% ⁴⁶ ; fatigue 35% to 58%,^46,47 (grade 3 or 4) 4% to 6%^46,47; fever 19%, ⁴⁶ (grade 3 or 4) 1%. ⁴⁶
• C.Gastrointestinal: Anorexia 39% to 62%,^46,47 (grade 3 or 4) 4%^46,47; diarrhea 32% to 38%,^46,47 (grade 3 or 4) 3% to 6%^46,47; nausea 48% to 65%,^46.47 (grade 3 or 4) 2% to 4%^46,47; stomatitis 8%, ⁴⁶ (grade 3 or 4) <1% ⁴⁶ ; vomiting 28% to 34%,^46,47 (grade 3 or 4) 2% to 4%.^46,47
• D.Hematologic: Anemia 73% to 77%,^46,47 (grade 3 or 4) 17% to 18%^46,47; febrile neutropenia (grade 3) 11%, ⁴⁸ (grade 3 or 4) 4%^46,47; leucopenia 76% to 77%,^46,47 (grade 3 or 4) 21% to 28%^46,47; lymphopenia 35%, (grade 3 or 4) 10% ⁴⁷ ; neutropenia 67% to 72%, ⁴⁷ (grade 3) 58%, ⁴⁸ (grade 3 or 4) 38% to 50%^46,47; thrombocytopenia 39% to 42%,^46,47 (grade 3 or 4) 4% to 5%.^46,47
• E.Hepatic: Increased ALT 24%, ⁴⁶ (grade 3 or 4) 2% ⁴⁶ ; increased AST 30%, ⁴⁶ (grade 3 or 4) 4% ⁴⁶ ; increased AP 39%, ⁴⁶ (grade 3 or 4) 8% ⁴⁶ ; increased bilirubin 36%, ⁴⁶ (grade 3 or 4) 9%. ⁴⁶
• F.Neurologic: Hand-foot syndrome 2%. ⁴⁶
• G.Pain: Abdominal 21%, ⁴⁶ (grade 3 or 4) 2%. ⁴⁶
• H.Renal: Increased creatinine 13%, ⁴⁶ (grade 3 or 4) <1%. ⁴⁶

Dose Adjustment

• A. Hepatic ⁴⁵
  • 1.Total bilirubin less than or equal to the ULN and AST greater than ULN, no adjustment required.
  • 2.Total bilirubin less than 1.5 times the ULN, and any AST, no adjustment required.
  • 3.Total bilirubin greater than 1.5 to 3 times ULN and any AST, no information available.
  • 4.Total bilirubin greater than 3 times ULN and any AST, no information available.
• B. Renal ⁴⁵
  • 1.Creatinine clearance (CL_cr) greater than or equal to 30 mL/min and less than or equal to 89 mL/min, no adjustment required.
  • 2.Moderate renal impairment, dose adjustment may be required to minimize toxicity.
  • 3.CL_cr less than 30 mL/min, no information available.