Drug information of talazoparib

Talazoparib is a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor, including PARP1 and PARP2. PARP enzymes are involved in DNA transcription, cell cycle regulation, and DNA repair. Talazoparib is a potent PARP inhibitor, with both strong catalytic inhibition and a PARP-trapping potential that is significantly greater than other PARP inhibitors. Catalytic inhibition causes cell death due to accumulation of irreparable DNA damage; talazoparib also traps PARP-DNA complexes, which may be more effective in cell death than enzymatic inhibition alone .

Talazoparib prevents PARP-mediated repair of DNA damage in cancer cells, allowing accumulation of damage and PARP-DNA complexes.

Peak plasma concentration, steady-state: 16.4 ng/mL

Peak plasma time: 1-2 hr

AUC, steady-state: 208 ng·hr/mL

Steady-state reached within 2-3 weeks

Food effect: Following a single oral 0.5-mg dose with high-fat, high-calorie food (~800-1000 calories with 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively), mean peak plasma concentration of talazoparib was decreased by 46%, the median peak plasma time was delayed from 1-4 hr, and AUC was not affected

Vd: 420 L

Protein bound: 74%

Metabolism: Undergoes minimal hepatic metabolism.Identified metabolic pathways of talazoparib in humans include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation.

Half-life: 90 hr

Clearance: 6.45 L/hr

Excretion: Urine (~68.7% [54.6% unchanged]), feces (19.7% [13.6% unchanged])

Breast cancer, locally advanced or metastatic (BRCA-mutated, HER2-negative)

1 mg PO qDay with or without food

Continue until disease progression or unacceptable toxicity occurs

Recommended talazoparib dose reductions for toxicity:

Initial/usual starting dose: 1 mg once daily

First dose reduction: 0.75 mg once daily

Second dose reduction: 0.5 mg once daily

Third dose reduction: 0.25 mg once daily

Hematologic toxicity:

Hemoglobin <8 g/dL: Withhold talazoparib until hemoglobin is ≥9 g/dL, then resume therapy at a reduced dose.

Neutrophils <1,000/mm³: Withhold talazoparib until neutrophils are ≥1,500/mm³, then resume therapy at a reduced dose.

Platelets <50,000/mm³: Withhold talazoparib until platelets are ≥75,000/mm³, then resume therapy at a reduced dose.

MDS/AML (confirmed): Discontinue therapy

Nonhematologic toxicity: Grade 3 or 4 toxicity: Withhold talazoparib until toxicity is ≤ grade 1, then consider resuming therapy at a reduced dose or discontinuing talazoparib (depending on the severity of the toxicity).

Coadministration with P-glycoprotein (P-gp) inhibitors: P-gp inhibitors (ie, amiodarone, carvedilol, clarithromycin, itraconazole, verapamil): Avoid use; if coadministration cannot be avoided, reduce talazoparib dose to 0.75 mg qDay.

Renal impairment

• Mild (CrCl 60-89 mL/min): No dosage adjustment required
• Moderate (CrCl 30-59 mL/min): Reduce dose to 0.75 mg qDay
• Severe (CrCl 15-29 mL/min): Reduce dose to 0.5 mg qDay

None

Decreased hemoglobin -Decreased leukocytes -Decreased lymphocytes -Decreased neutrophils -Fatigue -Decreased platelets -Increased glucose -Anemia -Nausea -Increased AST -Increased alkaline phosphatase -Neutropenia -Increased ALT -Headache -Decreased calcium - Vomiting -Alopecia -Diarrhea -Decreased appetite -Abdominal pain -Dizziness - Dysgeusia -Dyspepsia -Stomatitis -Lymphopenia -Bone marrow depression-Acute myelocytic leukemia, myelodysplastic syndrome

-Myelosuppression (eg, anemia, leukopenia/neutropenia, and/or thrombocytopenia) reported;

-Based on its mechanism of action and findings from animal data, fetal harm may occur when administered to a pregnant woman.

- Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) reported; If MDS/AML is confirmed, discontinue treatment.

-Coadministration with P-gp inhibitors (ie, amiodarone, carvedilol, clarithromycin, itraconazole, verapamil) may increase talazoparib exposure.

-Coadministration with BCRP inhibitors may increase talazoparib exposure.

-Nausea and vomiting (usually mild to moderate) may commonly occur; diarrhea may also occur.

- Talazoparib exposure is increased in patients with renal impairment. Dosage adjustment is recommended in patients with moderate to severe impairment

-monitor CBC count for cytopenia at baseline and monthly thereafter; do not start until patients have adequately recovered from hematological toxicity caused by previous therapy

-For prolonged hematological toxicities, interrupt and monitor blood cell counts weekly until recovery; if levels do not recover after 4 weeks, refer patient to a hematologist for further investigations.

-If a dose is missed or vomited, an additional dose should not be administered; administer the next dose at the usual scheduled time

-Administer orally with or without food

Based on findings from animal studies and its mechanism of action, embryo-fetal harm may occur when administered to a pregnant woman.

No data available on use in pregnant women to inform a drug-associated risk.

Recommend a pregnancy test for females of reproductive potential prior to initiating treatment.

Advise females of reproductive potential to use effective contraception during treatment and for ≥7 months following the last dose.

Based on genotoxicity and animal reproduction studies, advise males with female partners of reproductive potential and pregnant partners to use effective contraception during treatment and for ≥4 months following the last dose.

Based on animal studies, impaired fertility in males of reproductive potential may occur.