12.1 Mechanism of Action

Talazoparib is an inhibitor of 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 BRCA1 and BRCA2, 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 patient-derived xenograft breast cancer models bearing mutated BRCA1 or mutated BRCA2 or wild type BRCA1 and BRCA2.

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of TALZENNA have not been fully characterized.

Cardiac Electrophysiology

At a dose of 1 mg (the recommended dosage for treatment of breast cancer), TALZENNA had no large QTc prolongation (i.e., >20 ms).

12.3 Pharmacokinetics

After administration of TALZENNA 1 mg orally once daily as a single agent (the recommended dosage for breast cancer), the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 173 (32%) ng.hr/mL and 19 (32%) ng/mL, respectively. The mean (CV%) steady-state Ctrough was 3.5 (61%) ng/mL.

After administration of TALZENNA 0.5 mg orally once daily (the recommended dosage for prostate cancer) with enzalutamide, the mean (CV%) steady-state Ctrough ranged from 3.3 to 3.7 ng/mL (45% to 48%).

The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to 2 mg (2 times the recommended dose for breast cancer). The median accumulation ratio of talazoparib following 1 mg orally once daily is 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within 2 to 3 weeks when administered as a single agent and within 9 weeks when coadministered with enzalutamide.

Absorption
The median time to Cmax (Tmax) was approximately 1 hour (range: 0.4 to 4 hours) after dosing.

Food Effect
Following administration of a TALZENNA 1 mg dose soft gelatin capsule with high-fat, high-calorie food (approximately 800 to 1,000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), the mean steady-state Cmax was decreased by 42%, the median Tmax was delayed from 1 to 4 hours, and AUC was not affected as compared to those under fasted conditions.

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) is 90 (±58) hours and the mean apparent oral clearance (inter-subject variability) is 6.5 L/h (31%).

Metabolism
Talazoparib undergoes minimal hepatic metabolism. The identified metabolic pathways 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 69% (55% unchanged) of the total administered radiolabeled dose of talazoparib was recovered in urine, and 20% (14% 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 had no clinically significant effect on the PK of talazoparib.

Patients with Renal Impairment
Mild (eGFR 60 – 89 mL/min/1.73 m2) renal impairment had no clinically significant effect on talazoparib pharmacokinetics. Talazoparib steady-state total exposure (AUC) increased by 43% in subjects with moderate (eGFR 30 – 59 mL/min/1.73 m2) renal impairment and 163% in patients with severe (eGFR 15 – 29 mL/min/1.73 m2) renal impairment relative to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). Talazoparib steady-state peak concentration (Cmax) increased by 32% in subjects with moderate renal impairment and 89% in subjects with severe renal impairment, relative to subjects with normal renal function. Similar increases in AUC were observed with talazoparib when given with enzalutamide for patients with moderate and severe renal impairment. 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
Clinical Studies
Effect of P-gp Inhibitors: Coadministration of a P-gp inhibitor (itraconazole) with a single 0.5 mg dose of TALZENNA increased talazoparib AUC and Cmax by approximately 56% and 40%, respectively. Coadministration with the following other P-gp inhibitors: amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil increased talazoparib exposure by 45%.

Coadministration with other P-gp inhibitors (including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin) had no clinically significant effect on talazoparib pharmacokinetics.

Effect of P-gp Inducers: Coadministration of a P-gp inducer (rifampin) with a single 1 mg dose of TALZENNA increased talazoparib Cmax by 37% with no effect on talazoparib AUC.

Effect of Acid-Reducing Agents: 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.

Enzalutamide: Coadministration of enzalutamide with TALZENNA increased talazoparib exposure approximately 2-fold.

In Vitro Studies
Transporters: Talazoparib is a substrate of P-gp and BCRP transporters, but not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, or MATE2-K.

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

CYP Enzymes: Talazoparib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.

Talazoparib is not an inducer of CYP1A2, CYP2B6, or CYP3A4.

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