TALZENNA 10 Action And Clinical Pharmacology

talazoparib

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10.1 Mechanism of Action

TALZENNA is an inhibitor of poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) enzymes, PARP1, and PARP2. PARP enzymes are involved in cellular DNA damage response signaling pathways such as DNA repair, gene transcription, cell cycle regulation, and cell death. PARP inhibitors (PARPi) exert cytotoxic effects on cancer cells by 2 mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby PARP protein bound to a PARPi does not readily dissociate from a DNA lesion, thus preventing DNA repair, replication, and transcription and ultimately leading to apoptosis and/or cell death. Treatment of cancer cell lines that are harboring defects in DNA repair genes with talazoparib single agent leads to double strand DNA breaks, resulting in decreased cell proliferation and increased apoptosis. The cytotoxicity observed with talazoparib against multiple tumor cell lines harboring mutations in the DNA damage response pathways, can be attributed to its inhibition of PARP catalytic activity and PARP trapping. Talazoparib anti-tumor activity was also observed in the patient-derived xenograft BRCA1 or BRCA2-mutant breast cancer models.

10.2 Pharmacodynamics

Cardiac electrophysiology 
The effect of talazoparib on cardiac repolarization was evaluated using time-matched electrocardiograms (ECGs) in assessing the relationship between the change of the QT interval corrected for heart rate (QTc) from baseline and the corresponding plasma talazoparib concentrations in 37 patients with advanced solid tumors. Talazoparib did not have a clinically relevant effect on QTc prolongation at the maximum clinically recommended dose of 1 mg once daily.

10.3 Pharmacokinetics

Talazoparib exposure generally increased proportionally with dose across the range of 0.025 mg to 2 mg after daily administration of multiple doses. Following repeated daily dosing of 1 mg talazoparib to patients, the geometric mean area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was in the range of 126 ng•hr/mL to 208 ng•hr/mL and 11.4 ng/mL to 19.1 ng/mL, respectively. Following repeated daily dosing, talazoparib plasma concentrations reached steady-state within 2 to 3 weeks. The median accumulation ratio of talazoparib following repeated oral administration of 1 mg once daily was in the range of 2.33 to 5.15.

Table 8 - Summary of Talazoparib Pharmacokinetic Parameters in Patients with Advanced Cancer
 Cmax 
(ng/mL)a
Tmax 
(h)c
t½  
(h)b
AUCinf  
(ng·h/mL)a
CL/F 
(L/h)a
Vz/F  
(L)a
Single dose mean4.35 to 8.791.0 (0.5-2.0)62.4 to 89.8116 to 1965.12 to 7.71447 to 847
 

Summary statistics based on pharmacokinetic parameters of talazoparib following administration of a single 1 mg dose of talazoparib from 4 studies in cancer patients.

a

For Cmax, AUC, CL/F, and Vz/F geometric mean is shown

b

For t ½ mean range is shown

c

For tmax median (range) is shown

Absorption: Following oral administration of talazoparib, the median time to Cmax (Tmax) was generally between 1 to 2 hours after dosing under fasting conditions. An absolute bioavailability study has not been conducted in humans. However, based on urinary excretion data the absolute bioavailability is at least 54.6% with fraction absorbed of at least 68.7% (see Elimination).

The effect of food 
Food intake decreased the rate but not the extent of talazoparib absorption. Following a single oral dose of talazoparib with high-fat, high-calorie food (approximately 827 calories, 57% fat), the mean Cmax of talazoparib was decreased by approximately 46%, the median Tmax was delayed from 1 to 4 hours, while the AUCinf was not affected. Based on these results, TALZENNA can be administered with or without food.

Distribution: The population mean apparent volume of distribution (Vss/F) of talazoparib was 420 L. In vitro, talazoparib is approximately 74% bound to plasma proteins with no concentration dependence over the concentration range of 0.01 µM to 1 µM. Renal or hepatic impairment does not appear to impact talazoparib protein binding as there was no obvious trend in the mean talazoparib fraction of unbound drug (fu) in human plasma in vivo with worsening renal or hepatic function.

Metabolism: Talazoparib undergoes minimal hepatic metabolism in humans. Following oral administration of a single 1 mg dose of [14C]talazoparib to humans, no major circulating metabolites were identified in plasma, and talazoparib was the only circulating drug-derived entity identified. No metabolites that individually represented more than 10% of the administered dose were recovered in the urine or feces. The identified metabolic pathways of talazoparib in humans include: 1) mono-oxidation; 2) dehydrogenation; 3) cysteine conjugation of mono-desfluoro-talazoparib; and 4) glucuronide conjugation.

In vitro, talazoparib was not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 or inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

In vitro, talazoparib did not inhibit any of the major intestinal, hepatic or renal membrane transporters (P-gp, BCRP, 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) at clinically relevant concentrations.

In vitro, talazoparib did not inhibit any of the major uridine-diphosphate glucuronosyltransferase (UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15) at clinically relevant concentrations.

Elimination: The mean terminal plasma half-life of talazoparib was 89.8 hours and the population mean apparent oral clearance (CL/F) was 6.45 L/h in cancer patients. In 6 female patients with advanced solid tumors given a single oral dose of [14C]talazoparib, a mean of 68.7% and 19.7% of the total administered radioactive dose was recovered in urine and feces, respectively. Excretion of unchanged talazoparib in urine was the major route of elimination accounting for 54.6% of the administered dose, while unchanged talazoparib recovered in the feces accounted for 13.6%.

Special Populations and Conditions

Pediatrics: Pharmacokinetics of talazoparib have not been evaluated in patients < 18 years of age.

Age: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of age (ranging from 18 to 88 years) on the PK of talazoparib. The results have shown that age had no clinically relevant effect on the PK of talazoparib.

Sex: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of sex (53 males and 437 females) on the PK of talazoparib. The results have shown that sex had no clinically relevant effect on the PK of talazoparib.

Pregnancy and Breast-feeding: There are no data from the use of TALZENNA in pregnant women. Studies in animals have shown genotoxicity and embryo-fetal toxicity (see Section 16 Non-Clinical Toxicology). TALZENNA can cause fetal harm when administered to a pregnant woman. It is unknown whether TALZENNA is excreted in human breast milk. A risk to newborns/infants cannot be excluded and therefore breastfeeding is not recommended during treatment with TALZENNA and for at least 1 month after the final dose.

Race: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of race (361 White, 41 Asian, 16 Black, 9 Others, and 63 Not reported) on the PK of talazoparib. The results have shown that ethnicity had no clinically relevant effect on the PK of talazoparib.

Hepatic Insufficiency: Based on a population PK analysis that included 490 patients, where 118 patients had mild hepatic impairment (total bilirubin ≤ 1.0 × ULN and AST > ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the PK of talazoparib. The PK of talazoparib in patients with normal hepatic function, mild hepatic impairment, moderate hepatic impairment (total bilirubin >1.5 to 3.0 × ULN and any AST), or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST) was studied in a PK trial. Population PK analysis using data from this PK trial indicated that mild, moderate, or severe hepatic impairment had no significant impact on the PK of talazoparib.

Renal Insufficiency: Data from a PK trial in advanced cancer patients with varying degrees of renal impairment indicate that talazoparib total exposure (AUC0-24) after multiple talazoparib once-daily doses did not change and increased by 85%, and 167% in patients with mild (60 mL/min ≤ CrCL <90 mL/min), moderate (30 mL/min ≤ CrCL <60 mL/min) and severe (15 mL/min ≤ CrCL < 30 mL/min) renal impairment, respectively, relative to patients with normal renal function (CrCL ≥90mL/min). Talazoparib Cmax increased by 8%, 86%, and 93% in patients with mild, moderate, and severe renal impairment, respectively, relative to patients with normal renal function. Consistent with these findings, a population PK analysis that included 490 patients, where 132 patients had mild renal impairment, 33 patients had moderate renal impairment, and 1 patient had severe renal impairment, showed that talazoparib CL/F was decreased by 14.4% and 37.1% in patients with mild and moderate renal impairment, corresponding to 17% and 59% increase in AUC, respectively, when compared to patients with normal renal function. The PK of talazoparib has not been studied in patients requiring hemodialysis.

Obesity: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of body weight (ranging from 35.7 kg to 162 kg) on the PK of talazoparib. The results have shown that body weight had no clinically relevant effect on the PK of talazoparib.

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10 Action And Clinical Pharmacology

10.1 Mechanism of Action

TALZENNA is an inhibitor of poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) enzymes, PARP1, and PARP2. PARP enzymes are involved in cellular DNA damage response signaling pathways such as DNA repair, gene transcription, cell cycle regulation, and cell death. PARP inhibitors (PARPi) exert cytotoxic effects on cancer cells by 2 mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby PARP protein bound to a PARPi does not readily dissociate from a DNA lesion, thus preventing DNA repair, replication, and transcription and ultimately leading to apoptosis and/or cell death. Treatment of cancer cell lines that are harboring defects in DNA repair genes with talazoparib single agent leads to double strand DNA breaks, resulting in decreased cell proliferation and increased apoptosis. The cytotoxicity observed with talazoparib against multiple tumor cell lines harboring mutations in the DNA damage response pathways, can be attributed to its inhibition of PARP catalytic activity and PARP trapping. Talazoparib anti-tumor activity was also observed in the patient-derived xenograft BRCA1 or BRCA2-mutant breast cancer models.

10.2 Pharmacodynamics

Cardiac electrophysiology 
The effect of talazoparib on cardiac repolarization was evaluated using time-matched electrocardiograms (ECGs) in assessing the relationship between the change of the QT interval corrected for heart rate (QTc) from baseline and the corresponding plasma talazoparib concentrations in 37 patients with advanced solid tumors. Talazoparib did not have a clinically relevant effect on QTc prolongation at the maximum clinically recommended dose of 1 mg once daily.

10.3 Pharmacokinetics

Talazoparib exposure generally increased proportionally with dose across the range of 0.025 mg to 2 mg after daily administration of multiple doses. Following repeated daily dosing of 1 mg talazoparib to patients, the geometric mean area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was in the range of 126 ng•hr/mL to 208 ng•hr/mL and 11.4 ng/mL to 19.1 ng/mL, respectively. Following repeated daily dosing, talazoparib plasma concentrations reached steady-state within 2 to 3 weeks. The median accumulation ratio of talazoparib following repeated oral administration of 1 mg once daily was in the range of 2.33 to 5.15.

Table 8 - Summary of Talazoparib Pharmacokinetic Parameters in Patients with Advanced Cancer
 Cmax 
(ng/mL)a
Tmax 
(h)c
t½  
(h)b
AUCinf  
(ng·h/mL)a
CL/F 
(L/h)a
Vz/F  
(L)a
Single dose mean4.35 to 8.791.0 (0.5-2.0)62.4 to 89.8116 to 1965.12 to 7.71447 to 847
 

Summary statistics based on pharmacokinetic parameters of talazoparib following administration of a single 1 mg dose of talazoparib from 4 studies in cancer patients.

a

For Cmax, AUC, CL/F, and Vz/F geometric mean is shown

b

For t ½ mean range is shown

c

For tmax median (range) is shown

Absorption: Following oral administration of talazoparib, the median time to Cmax (Tmax) was generally between 1 to 2 hours after dosing under fasting conditions. An absolute bioavailability study has not been conducted in humans. However, based on urinary excretion data the absolute bioavailability is at least 54.6% with fraction absorbed of at least 68.7% (see Elimination).

The effect of food 
Food intake decreased the rate but not the extent of talazoparib absorption. Following a single oral dose of talazoparib with high-fat, high-calorie food (approximately 827 calories, 57% fat), the mean Cmax of talazoparib was decreased by approximately 46%, the median Tmax was delayed from 1 to 4 hours, while the AUCinf was not affected. Based on these results, TALZENNA can be administered with or without food.

Distribution: The population mean apparent volume of distribution (Vss/F) of talazoparib was 420 L. In vitro, talazoparib is approximately 74% bound to plasma proteins with no concentration dependence over the concentration range of 0.01 µM to 1 µM. Renal or hepatic impairment does not appear to impact talazoparib protein binding as there was no obvious trend in the mean talazoparib fraction of unbound drug (fu) in human plasma in vivo with worsening renal or hepatic function.

Metabolism: Talazoparib undergoes minimal hepatic metabolism in humans. Following oral administration of a single 1 mg dose of [14C]talazoparib to humans, no major circulating metabolites were identified in plasma, and talazoparib was the only circulating drug-derived entity identified. No metabolites that individually represented more than 10% of the administered dose were recovered in the urine or feces. The identified metabolic pathways of talazoparib in humans include: 1) mono-oxidation; 2) dehydrogenation; 3) cysteine conjugation of mono-desfluoro-talazoparib; and 4) glucuronide conjugation.

In vitro, talazoparib was not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 or inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

In vitro, talazoparib did not inhibit any of the major intestinal, hepatic or renal membrane transporters (P-gp, BCRP, 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) at clinically relevant concentrations.

In vitro, talazoparib did not inhibit any of the major uridine-diphosphate glucuronosyltransferase (UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15) at clinically relevant concentrations.

Elimination: The mean terminal plasma half-life of talazoparib was 89.8 hours and the population mean apparent oral clearance (CL/F) was 6.45 L/h in cancer patients. In 6 female patients with advanced solid tumors given a single oral dose of [14C]talazoparib, a mean of 68.7% and 19.7% of the total administered radioactive dose was recovered in urine and feces, respectively. Excretion of unchanged talazoparib in urine was the major route of elimination accounting for 54.6% of the administered dose, while unchanged talazoparib recovered in the feces accounted for 13.6%.

Special Populations and Conditions

Pediatrics: Pharmacokinetics of talazoparib have not been evaluated in patients < 18 years of age.

Age: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of age (ranging from 18 to 88 years) on the PK of talazoparib. The results have shown that age had no clinically relevant effect on the PK of talazoparib.

Sex: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of sex (53 males and 437 females) on the PK of talazoparib. The results have shown that sex had no clinically relevant effect on the PK of talazoparib.

Pregnancy and Breast-feeding: There are no data from the use of TALZENNA in pregnant women. Studies in animals have shown genotoxicity and embryo-fetal toxicity (see Section 16 Non-Clinical Toxicology). TALZENNA can cause fetal harm when administered to a pregnant woman. It is unknown whether TALZENNA is excreted in human breast milk. A risk to newborns/infants cannot be excluded and therefore breastfeeding is not recommended during treatment with TALZENNA and for at least 1 month after the final dose.

Race: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of race (361 White, 41 Asian, 16 Black, 9 Others, and 63 Not reported) on the PK of talazoparib. The results have shown that ethnicity had no clinically relevant effect on the PK of talazoparib.

Hepatic Insufficiency: Based on a population PK analysis that included 490 patients, where 118 patients had mild hepatic impairment (total bilirubin ≤ 1.0 × ULN and AST > ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the PK of talazoparib. The PK of talazoparib in patients with normal hepatic function, mild hepatic impairment, moderate hepatic impairment (total bilirubin >1.5 to 3.0 × ULN and any AST), or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST) was studied in a PK trial. Population PK analysis using data from this PK trial indicated that mild, moderate, or severe hepatic impairment had no significant impact on the PK of talazoparib.

Renal Insufficiency: Data from a PK trial in advanced cancer patients with varying degrees of renal impairment indicate that talazoparib total exposure (AUC0-24) after multiple talazoparib once-daily doses did not change and increased by 85%, and 167% in patients with mild (60 mL/min ≤ CrCL <90 mL/min), moderate (30 mL/min ≤ CrCL <60 mL/min) and severe (15 mL/min ≤ CrCL < 30 mL/min) renal impairment, respectively, relative to patients with normal renal function (CrCL ≥90mL/min). Talazoparib Cmax increased by 8%, 86%, and 93% in patients with mild, moderate, and severe renal impairment, respectively, relative to patients with normal renal function. Consistent with these findings, a population PK analysis that included 490 patients, where 132 patients had mild renal impairment, 33 patients had moderate renal impairment, and 1 patient had severe renal impairment, showed that talazoparib CL/F was decreased by 14.4% and 37.1% in patients with mild and moderate renal impairment, corresponding to 17% and 59% increase in AUC, respectively, when compared to patients with normal renal function. The PK of talazoparib has not been studied in patients requiring hemodialysis.

Obesity: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of body weight (ranging from 35.7 kg to 162 kg) on the PK of talazoparib. The results have shown that body weight had no clinically relevant effect on the PK of talazoparib.

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