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TALZENNA Clinical Pharmacology (talazoparib)


12.1 Mechanism of Action

Talazoparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2, which play a role in DNA repair. In vitro studies with cancer cell lines that harbored defects in DNA repair genes, including BRCA 1 and BRCA 2, have shown that talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis. Talazoparib anti-tumor activity was observed in human patient-derived xenograft breast cancer tumor models bearing mutated BRCA 1 or mutated BRCA 2 or wild-type BRCA 1 and BRCA 2.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of talazoparib on cardiac repolarization was evaluated in 37 patients with advanced solid tumors. Talazoparib had no large QTc prolongation (i.e., >20 ms) at the recommended dose.

12.3 Pharmacokinetics

After oral administration of 1 mg TALZENNA once daily in patients, the recommended dose, the geometric mean [% coefficient of variation (CV%)] of AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 208 (37%) and 16.4 (32%) ng/mL, respectively. The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to 2 mg (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.


Following oral administration of talazoparib, the median time to Cmax (Tmax) was generally between 1 to 2 hours after dosing.

Food Effect

Following a single oral dose of 0.5 mg TALZENNA with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), the mean Cmax of talazoparib was decreased by 46%, the median Tmax was delayed from 1 to 4 hours, and AUCinf was not affected.


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.


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.


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 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.

Specific Populations

Age (18 to 88 years), sex, race (361 White, 41 Asian, 16 Black, 9 Others, and 63 Not Reported), body weight (36 to 162 kg), and mild to severe hepatic impairment based on NCI criteria had no clinically relevant effect on the PK of talazoparib.

Pediatric Patients

The PK of talazoparib have not been evaluated in patients <18 years of age.

Patients with Renal Impairment

Talazoparib steady-state total exposure (AUC0–24) increased by 12%, 43%, and 163% in patients with mild (eGFR 60 – 89 mL/min/1.73 m2), moderate (eGFR 30 – 59 mL/min/1.73 m2), and severe (eGFR 15 – 29 mL/min/1.73 m2) renal impairment, respectively, relative to patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). Talazoparib steady-state peak concentration (Cmax) increased by 11%, 32%, and 89% in patients with mild, moderate, and severe renal impairment, respectively, relative to patients with normal renal function. The PK of talazoparib has not been studied in patients requiring hemodialysis. There was no evidence of a relationship between the protein binding of talazoparib and renal function.

Drug Interaction Studies

Effect of Other Drugs on Talazoparib

Effect of P-gp inhibitors: In patients with advanced solid tumors, coadministration of a P-gp inhibitor (multiple 100 mg twice-daily doses of itraconazole) with a single 0.5 mg talazoparib dose increased talazoparib AUCinf and Cmax by approximately 56% and 40%, respectively. Population PK analysis showed that coadministration with P-gp inhibitors including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil in clinical studies increased talazoparib exposure by 45% [see Dosage and Administration (2.5), Drug Interactions (7.1)].

Coadministration with P-gp inhibitors including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin in clinical studies increased talazoparib exposure by 8% [see Dosage and Administration (2.5), Drug Interactions (7)].

Effect of P-gp inducers: In patients with advanced solid tumors, coadministration of a P-gp inducer (multiple 600 mg once-daily doses of rifampin) with a single 1 mg talazoparib dose increased talazoparib Cmax by 37% with no effect on talazoparib exposure.

Effect of BCRP inhibitors: The effect of BCRP inhibitors on PK of talazoparib has not been studied. Coadministration with BCRP inhibitors may increase talazoparib exposure [see Drug Interactions (7)].

Effect of acid-reducing agents on talazoparib: Coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor 2 antagonists (H2RA), or other acid reducing agents has no effect on the absorption of talazoparib.

In Vitro Studies

Talazoparib is a substrate of P-gp and BCRP transporters.

Talazoparib is not a substrate of organic anion transporting polypeptide [OATP]1B1, OATP1B3, organic cationic transporter [OCT]1, OCT2, organic anion transporter [OAT]1, OAT3, bile salt export pump [BSEP], multidrug and toxin extrusion [MATE]1, and MATE2-K.

Talazoparib is not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5, or inducer of CYP1A2, CYP2B6, or CYP3A4.

Talazoparib is not an inhibitor of transporters including P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, and MATE2-K.

Talazoparib is not an inhibitor of uridine-diphosphate glucuronosyltransferase (UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15).

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