jueves, 8 de noviembre de 2018

Clinical Pharmacology Corner: FDA Approves TALZENNA (Talazoparib)

FDA Approves TALZENNA (Talazoparib) for the Treatment of Deleterious or Suspected Deleterious Germline BRCA-mutated (gBRCAm) HER2 Negative Locally Advanced or Metastatic Breast Cancer in Adults 

On October 16, 2018, the U.S. Food and Drug Administration (FDA) approved TALZENNA (talazoparib) for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2 negative locally advanced or metastatic breast cancer. Select patients for the treatment of advanced breast cancer with TALZENNA based on the presence of germline BRCA mutations. Information on the FDA-approved test for the detection of BRCA mutations is available at http://www.fda.gov/companiondiagnostics. The approved recommended dose of TALZENNA is 1 mg taken as a single oral daily dose, with or without food. For patients with moderate (CLcr 30-59 mL/min) renal impairment or concurrently taking certain P-gp inhibitors, the recommended dose of TALZENNA is 0.75 mg once daily.
Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is confirmed. Additional information regarding recommended dosage modifications, warnings, and precautions can be found in the full prescribing information linked below.
Based on its mechanism of action and findings from animal data, TALZENNA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Recommendations for patients and partners of reproductive potential can be found in the full prescribing information linked below. Advise women not to breastfeed.
Mechanism of Action (MOA) and Pharmacokinetics (PK)
  • MOA: Talazoparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2.
  • General PK: The PK of talazoparib are linear from 0.025 mg to 2 mg (0.025 to 2 times the recommended dose). The median accumulation ratio of talazoparib following repeated oral administration of 1 mg once daily was in the range of 2.3 to 5.2. Talazoparib plasma concentrations reached steady state within 2 to 3 weeks.
  • Absorption: Following oral administration of talazoparib, the median time to Cmax (Tmax) was approximately 1 to 2 hours after dosing. 
  • Distribution: The mean apparent volume of distribution of talazoparib is 420 L. In vitro, protein binding of talazoparib is 74% and is independent of talazoparib concentration.
  • Elimination: The mean terminal plasma half life (± standard deviation) of talazoparib is 90 (± 58) hours, and the mean apparent oral clearance (% inter-subject variability) is 6.45 L/h (31.1%) in cancer patients.
  • Metabolism: Talazoparib undergoes minimal hepatic metabolism. The identified metabolic pathways of talazoparib in humans include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation.
  • Excretion: Excretion of talazoparib in urine was the major route of elimination. Approximately 68.7% (54.6% unchanged) of the total administered radioactive dose [14C]-talazoparib was recovered in urine, and 19.7% (13.6% unchanged) was recovered in feces.
Drug Interactions
  • P-gp Inhibitors: Coadministration with P-gp inhibitors may increase talazoparib exposure. Reduce TALZENNA dose for certain P-gp inhibitors and monitor for potential increased adverse reactions as appropriate. 
  • BCRP Inhibitors: Coadministration with BCRP inhibitors may increase talazoparib exposure. If coadministration cannot be avoided, monitor for potential increased adverse reactions.
Use in Specific Populations
No clinically significant differences in the PK of talazoparib were observed based on age (18-88 years), sex, race/ethnicity, and body weight. Mild (total bilirubin ≤ 1.0 × ULN and AST > ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST)  hepatic impairment had no effect on the PK of talazoparib. The PK of talazoparib have not been evaluated in patients < 18 years of age or in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN and any AST) or severe (total bilirubin > 3.0 × ULN and any AST) hepatic impairment. 
Patients with Renal Impairment
Talazoparib CL/F was decreased by 14.4% in patients with mild (CLcr 60-89 mL/min) renal impairment and 37.1% in patients with moderate (CLcr 30-59 mL/min)  renal impairment, when compared to patients with normal (CLcr ≥ 90 mL/min) renal function. Reduce the recommended dose of TALZENNA in patients with moderate renal impairment.
The PK of talazoparib have not been studied in patients with severe (CLcr < 30 mL/min) renal impairment or in patients requiring hemodialysis. 
Efficacy and Safety
Efficacy of TALZENNA was demonstrated at the recommended dosage in an open-label, randomized, stratified study that enrolled patients with gBRCAm HER2 negative locally advanced or metastatic breast cancer. The major efficacy outcome measure was progression-free survival (PFS). Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.
Most common (≥ 20%) adverse reactions of any grade were: Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite. The most common laboratory abnormalities (≥ 25%) were: Decreases in hemoglobin, platelets, neutrophils, lymphocytes, leukocytes, and calcium, and increases in glucose, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. 
Full  prescribing information is available at https://go.usa.gov/xPR7p.
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.
A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA

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