IBRANCE Action And Clinical Pharmacology

palbociclib

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Mechanism of Action 
Palbociclib is a selective, reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D and CDK4/6 are downstream of multiple signaling pathways which lead to cellular proliferation. Through inhibition of cyclin D-CDK4/6 complex activity, palbociclib inhibits the phosphorylation of retinoblastoma (Rb) protein, blocking cell cycle progression from G1 into S phase. In a panel of molecularly profiled breast cancer cell lines, palbociclib exhibited the greatest efficacy towards the luminal ER-positive subtype; particularly, in cell lines with increased Rb and cyclin D1 and decreased p16 gene expression. In combination with anti-estrogen agents, palbociclib demonstrated enhanced inhibition of cell proliferation and induction of cell senescence in ER-positive breast cancer models.

Pharmacodynamics

Cardiac Electrophysiology

The effect of palbociclib in combination with letrozole on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline at 5 timepoints during the dosing interval at steady-state in 77 patients with breast cancer. The exposure/response analysis showed a slight positive linear relationship between QTcF and palbociclib concentration, with a mean QTcF increase of 4.14 msec at the mean steady-state palbociclib Cmax, and an upper bound of the 1-sided 95% CI <7 msec. No patients had a post-baseline absolute mean maximum QTcF ≥480 msec or an increase from QTcF time-matched baseline value ≥60 msec during the QTc assessment period. The proportions of patients with observed changes from baseline in QTc parameters between 30 and 60 msec were comparable between the palbociclib plus letrozole and placebo plus letrozole arms. These data suggested that palbociclib, at the recommended dosing regimen of 125 mg daily, when added to letrozole, had no large effect on QTc (>20 msec).

Pharmacokinetics

The pharmacokinetics of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects. Pharmacokinetic parameters of palbociclib and letrozole obtained from study A5481003 are shown in Table 8.

Table 8 Summary of Plasma Pharmacokinetic Parameters of Palbociclib (125 mg QD) and Letrozole (2.5 mg QD) at Steady State When Administered Alone or in Combination to Patients with Advanced Breast Cancer in the Phase 1 Portion of A5481003
Palbociclib PK Parameter Summary Statisticsa
Treatment

Cmax

(ng/mL)

AUC(0-24)

(ng.hr/mL)

Tmax

(hr)

t½

(hr)

CL/F (L/hr)VzF (L)

PLB alone (N=12)

PLB + LTZ (N=12)

116 (28)

108 (29)

1982 (29)

1933 (31)

7.9 (2.2-8.2)

7.9 (2.0-8.1)

28.8 (±5.0)

-

63.1 (29)

-

2583 (26)

-

Letrozole PK Parameter Summary Statisticsa

LTZ alone (N=12)

LTZ + PLB (N=12)

104 (31)

95.0 (27)

1936 (35)

1739 (30)

1.0 (0-4.4)

2.0 (0.8-4.1)

-

-

-

-

-

-

AUC(0-24)=area under the plasma concentration-time curve from time 0 to 24 hours after dosing; 
CL/F=apparent oral clearance; Cmax=maximum observed plasma concentration; CSR=Clinical Study Report; 
%CV=percent coefficient of variation; LTZ=letrozole; N=total number of patients in the treatment arm; 
PK=pharmacokinetic; PLB=Palbociclib; QD=once daily; Std Dev=standard deviation; Tmax=time to first occurrence of Cmax
t1/2=terminal plasma half-life; Vz/F=apparent volume of distribution. 
a. Geometric mean (geometric %CV) is shown for all PK parameters except median (range) for Tmax and arithmetic mean (±Std Dev) for t1/2.

Absorption: Following oral single-dose administration of IBRANCE capsules with food, the time to achieve Cmax (Tmax) of palbociclib was generally between 6 to 12 hours. The Tmax of palbociclib is generally observed between 4 to 12 hours following oral single-dose administration of IBRANCE tablets. The IBRANCE tablet administered either after an overnight fast, with a high‑fat high‑calorie meal or with a moderate-fat standard-calorie meal was bioequivalent to the IBRANCE capsule administered with a moderate‑fat standard‑calorie meal. The mean absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5-4.2).

Food effect:

Capsules: The effect of food on palbociclib exposure following administration of IBRANCE capsules was evaluated in healthy subjects. Compared to IBRANCE capsules given under overnight fasted conditions, AUCinf and Cmax of palbociclib increased by 21% and 38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 13% and 24% when moderate-fat food was given 1 hour before and 2 hours after IBRANCE capsule dosing. In addition, food intake significantly reduced the inter-subject and intra-subject variability of palbociclib exposure. Based on these results, IBRANCE capsules should be taken with food.

Tablets: The effect of food on palbociclib exposure following administration of IBRANCE tablets was evaluated in healthy subjects. Compared to IBRANCE tablets given under overnight fasted conditions, the AUCinf and Cmax of palbociclib increased by 22% and 26%, respectively, when IBRANCE tablets were given with a high-fat, high-calorie meal, and by 9% and 10%, respectively, when IBRANCE tablets were given with a moderate-fat, standard-calorie meal. Food intake had no significant impact on the variability of palbociclib exposure following administration with IBRANCE tablets. Based on these results, IBRANCE tablets may be taken with or without food.

Distribution: Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The mean fraction of unbound (fu) palbociclib in human plasma in vivo increased with worsening hepatic function. There was no obvious trend in the mean palbociclib fu in human plasma in vivo with worsening renal function. The geometric mean apparent volume of distribution (Vz/F) was 2583 L.

Metabolism: In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, the major primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma (23% of total radioactivity in plasma). The major circulating metabolite was a glucuronide conjugate of palbociclib (14.8% of total radioactivity in plasma), although it only represented 1.5% of the administered dose in the excreta. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 25.8% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant sulfotransferase (SULT) enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.

Excretion: The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.08 L/hr, and the mean plasma elimination half-life was 28.8 hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [14C]palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites. Excretion of unchanged palbociclib in feces and urine was 2.3% and 6.9% of the administered dose, respectively.

Special Populations and Conditions:

Age, Gender, and Body Weight

Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), sex had no effect on the exposure of palbociclib, and neither age nor body weight had a clinically important effect on the exposure of palbociclib.

Pediatric (< 18 years of age):

Based on the limited data submitted and reviewed by Health Canada, the safety and efficacy of IBRANCE in pediatric patients have not been established: Therefore, Health Canada has not authorized an indication for pediatric use.

In a Phase 1 pediatric study in 34 patients (≥4 years and ≤21 years of age) including 30 pediatric patients (≥4 years and ˂ 18 years of age) with progressive or refractory brain tumors (except low grade gliomas) with intact Rb protein, palbociclib was administered orally as a single agent at 50, 75, and 95 mg/m2 dose levels daily for the first 21 days of a 28-day cycle. The maximum tolerated dose was determined to be 75 mg/m2 daily for 21 days of a 28-day cycle. Following single and repeated doses, mean palbociclib Cmax and AUClast in the pediatric patients increased in approximately dose proportional manner. Palbociclib was absorbed with a median Tmax of 4 to 8 hours across the 50, 75, and 95 mg/m2 dose levels. The mean palbociclib Cmax and AUC24 at steady-state at the 75 mg/m2 dose level in the pediatric patients were 109 ng/mL and 1706 ng•hr/mL, respectively. The observed palbociclib steady-state exposure (Cmax and AUC24) at the 75 mg/m2 dose level in this study were similar to that observed in adult patients following daily 125 mg palbociclib doses.

Hepatic Impairment

A pharmacokinetic trial was conducted in subjects with varying degrees of hepatic function who were administered a single 75 mg dose of palbociclib. In this study, palbociclib unbound exposure (unbound AUCinf) decreased by 17% in subjects with mild hepatic impairment (Child-Pugh class A), and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, relative to subjects with normal hepatic function. Peak palbociclib unbound exposure (unbound Cmax) was increased by 7%, 38% and 72% for mild, moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function. In addition, based on a population pharmacokinetic analysis that included 183 patients with advanced cancer where 40 patients had mild hepatic impairment based on National Cancer institute (NCI) classification (total bilirubin ≤Upper Limit of normal (ULN) and Aspartate Aminotransferase (AST) >ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the pharmacokinetics (PK) of palbociclib.

Renal Impairment

A pharmacokinetic trial was conducted in subjects with varying degrees of renal function who were administered a single 125 mg dose of palbociclib. In this study, total palbociclib exposure (AUCinf) was increased by 39%, 42%, and 31% with mild (60 mL/min≤CrCl<90 mL/min), moderate (30 mL/min≤CrCl<60 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively, relative to subjects with normal (CrCl ≥90mL/min) renal function. Peak palbociclib exposure (Cmax) was increased by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. In addition, based on a population pharmacokinetic analysis that included 183 patients with advanced cancer where 73 patients had mild renal impairment and 29 patients had moderate renal impairment, mild and moderate renal impairment had no effect on the PK of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis.

Asian race

Data from a pharmacology study evaluating the effect of Japanese ethnicity on the PK of a single 125-mg oral palbociclib dose given to Japanese and non-Asian healthy volunteers indicate that palbociclib AUCinf and Cmax values were 30% and 35% higher, respectively, in Japanese subjects when compared with non-Asian subjects. However, this finding was not reproduced consistently in subsequent studies in Japanese or Asian breast cancer patients after multiple dosing. Based on an analysis of the cumulative pharmacokinetic, safety and efficacy data across Asian and non-Asian populations, no dose adjustment based on Asian race is considered necessary.

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Action And Clinical Pharmacology

Mechanism of Action 
Palbociclib is a selective, reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D and CDK4/6 are downstream of multiple signaling pathways which lead to cellular proliferation. Through inhibition of cyclin D-CDK4/6 complex activity, palbociclib inhibits the phosphorylation of retinoblastoma (Rb) protein, blocking cell cycle progression from G1 into S phase. In a panel of molecularly profiled breast cancer cell lines, palbociclib exhibited the greatest efficacy towards the luminal ER-positive subtype; particularly, in cell lines with increased Rb and cyclin D1 and decreased p16 gene expression. In combination with anti-estrogen agents, palbociclib demonstrated enhanced inhibition of cell proliferation and induction of cell senescence in ER-positive breast cancer models.

Pharmacodynamics

Cardiac Electrophysiology

The effect of palbociclib in combination with letrozole on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline at 5 timepoints during the dosing interval at steady-state in 77 patients with breast cancer. The exposure/response analysis showed a slight positive linear relationship between QTcF and palbociclib concentration, with a mean QTcF increase of 4.14 msec at the mean steady-state palbociclib Cmax, and an upper bound of the 1-sided 95% CI <7 msec. No patients had a post-baseline absolute mean maximum QTcF ≥480 msec or an increase from QTcF time-matched baseline value ≥60 msec during the QTc assessment period. The proportions of patients with observed changes from baseline in QTc parameters between 30 and 60 msec were comparable between the palbociclib plus letrozole and placebo plus letrozole arms. These data suggested that palbociclib, at the recommended dosing regimen of 125 mg daily, when added to letrozole, had no large effect on QTc (>20 msec).

Pharmacokinetics

The pharmacokinetics of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects. Pharmacokinetic parameters of palbociclib and letrozole obtained from study A5481003 are shown in Table 8.

Table 8 Summary of Plasma Pharmacokinetic Parameters of Palbociclib (125 mg QD) and Letrozole (2.5 mg QD) at Steady State When Administered Alone or in Combination to Patients with Advanced Breast Cancer in the Phase 1 Portion of A5481003
Palbociclib PK Parameter Summary Statisticsa
Treatment

Cmax

(ng/mL)

AUC(0-24)

(ng.hr/mL)

Tmax

(hr)

t½

(hr)

CL/F (L/hr)VzF (L)

PLB alone (N=12)

PLB + LTZ (N=12)

116 (28)

108 (29)

1982 (29)

1933 (31)

7.9 (2.2-8.2)

7.9 (2.0-8.1)

28.8 (±5.0)

-

63.1 (29)

-

2583 (26)

-

Letrozole PK Parameter Summary Statisticsa

LTZ alone (N=12)

LTZ + PLB (N=12)

104 (31)

95.0 (27)

1936 (35)

1739 (30)

1.0 (0-4.4)

2.0 (0.8-4.1)

-

-

-

-

-

-

AUC(0-24)=area under the plasma concentration-time curve from time 0 to 24 hours after dosing; 
CL/F=apparent oral clearance; Cmax=maximum observed plasma concentration; CSR=Clinical Study Report; 
%CV=percent coefficient of variation; LTZ=letrozole; N=total number of patients in the treatment arm; 
PK=pharmacokinetic; PLB=Palbociclib; QD=once daily; Std Dev=standard deviation; Tmax=time to first occurrence of Cmax
t1/2=terminal plasma half-life; Vz/F=apparent volume of distribution. 
a. Geometric mean (geometric %CV) is shown for all PK parameters except median (range) for Tmax and arithmetic mean (±Std Dev) for t1/2.

Absorption: Following oral single-dose administration of IBRANCE capsules with food, the time to achieve Cmax (Tmax) of palbociclib was generally between 6 to 12 hours. The Tmax of palbociclib is generally observed between 4 to 12 hours following oral single-dose administration of IBRANCE tablets. The IBRANCE tablet administered either after an overnight fast, with a high‑fat high‑calorie meal or with a moderate-fat standard-calorie meal was bioequivalent to the IBRANCE capsule administered with a moderate‑fat standard‑calorie meal. The mean absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5-4.2).

Food effect:

Capsules: The effect of food on palbociclib exposure following administration of IBRANCE capsules was evaluated in healthy subjects. Compared to IBRANCE capsules given under overnight fasted conditions, AUCinf and Cmax of palbociclib increased by 21% and 38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 13% and 24% when moderate-fat food was given 1 hour before and 2 hours after IBRANCE capsule dosing. In addition, food intake significantly reduced the inter-subject and intra-subject variability of palbociclib exposure. Based on these results, IBRANCE capsules should be taken with food.

Tablets: The effect of food on palbociclib exposure following administration of IBRANCE tablets was evaluated in healthy subjects. Compared to IBRANCE tablets given under overnight fasted conditions, the AUCinf and Cmax of palbociclib increased by 22% and 26%, respectively, when IBRANCE tablets were given with a high-fat, high-calorie meal, and by 9% and 10%, respectively, when IBRANCE tablets were given with a moderate-fat, standard-calorie meal. Food intake had no significant impact on the variability of palbociclib exposure following administration with IBRANCE tablets. Based on these results, IBRANCE tablets may be taken with or without food.

Distribution: Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The mean fraction of unbound (fu) palbociclib in human plasma in vivo increased with worsening hepatic function. There was no obvious trend in the mean palbociclib fu in human plasma in vivo with worsening renal function. The geometric mean apparent volume of distribution (Vz/F) was 2583 L.

Metabolism: In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, the major primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma (23% of total radioactivity in plasma). The major circulating metabolite was a glucuronide conjugate of palbociclib (14.8% of total radioactivity in plasma), although it only represented 1.5% of the administered dose in the excreta. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 25.8% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant sulfotransferase (SULT) enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.

Excretion: The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.08 L/hr, and the mean plasma elimination half-life was 28.8 hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [14C]palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites. Excretion of unchanged palbociclib in feces and urine was 2.3% and 6.9% of the administered dose, respectively.

Special Populations and Conditions:

Age, Gender, and Body Weight

Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), sex had no effect on the exposure of palbociclib, and neither age nor body weight had a clinically important effect on the exposure of palbociclib.

Pediatric (< 18 years of age):

Based on the limited data submitted and reviewed by Health Canada, the safety and efficacy of IBRANCE in pediatric patients have not been established: Therefore, Health Canada has not authorized an indication for pediatric use.

In a Phase 1 pediatric study in 34 patients (≥4 years and ≤21 years of age) including 30 pediatric patients (≥4 years and ˂ 18 years of age) with progressive or refractory brain tumors (except low grade gliomas) with intact Rb protein, palbociclib was administered orally as a single agent at 50, 75, and 95 mg/m2 dose levels daily for the first 21 days of a 28-day cycle. The maximum tolerated dose was determined to be 75 mg/m2 daily for 21 days of a 28-day cycle. Following single and repeated doses, mean palbociclib Cmax and AUClast in the pediatric patients increased in approximately dose proportional manner. Palbociclib was absorbed with a median Tmax of 4 to 8 hours across the 50, 75, and 95 mg/m2 dose levels. The mean palbociclib Cmax and AUC24 at steady-state at the 75 mg/m2 dose level in the pediatric patients were 109 ng/mL and 1706 ng•hr/mL, respectively. The observed palbociclib steady-state exposure (Cmax and AUC24) at the 75 mg/m2 dose level in this study were similar to that observed in adult patients following daily 125 mg palbociclib doses.

Hepatic Impairment

A pharmacokinetic trial was conducted in subjects with varying degrees of hepatic function who were administered a single 75 mg dose of palbociclib. In this study, palbociclib unbound exposure (unbound AUCinf) decreased by 17% in subjects with mild hepatic impairment (Child-Pugh class A), and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, relative to subjects with normal hepatic function. Peak palbociclib unbound exposure (unbound Cmax) was increased by 7%, 38% and 72% for mild, moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function. In addition, based on a population pharmacokinetic analysis that included 183 patients with advanced cancer where 40 patients had mild hepatic impairment based on National Cancer institute (NCI) classification (total bilirubin ≤Upper Limit of normal (ULN) and Aspartate Aminotransferase (AST) >ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the pharmacokinetics (PK) of palbociclib.

Renal Impairment

A pharmacokinetic trial was conducted in subjects with varying degrees of renal function who were administered a single 125 mg dose of palbociclib. In this study, total palbociclib exposure (AUCinf) was increased by 39%, 42%, and 31% with mild (60 mL/min≤CrCl<90 mL/min), moderate (30 mL/min≤CrCl<60 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively, relative to subjects with normal (CrCl ≥90mL/min) renal function. Peak palbociclib exposure (Cmax) was increased by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. In addition, based on a population pharmacokinetic analysis that included 183 patients with advanced cancer where 73 patients had mild renal impairment and 29 patients had moderate renal impairment, mild and moderate renal impairment had no effect on the PK of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis.

Asian race

Data from a pharmacology study evaluating the effect of Japanese ethnicity on the PK of a single 125-mg oral palbociclib dose given to Japanese and non-Asian healthy volunteers indicate that palbociclib AUCinf and Cmax values were 30% and 35% higher, respectively, in Japanese subjects when compared with non-Asian subjects. However, this finding was not reproduced consistently in subsequent studies in Japanese or Asian breast cancer patients after multiple dosing. Based on an analysis of the cumulative pharmacokinetic, safety and efficacy data across Asian and non-Asian populations, no dose adjustment based on Asian race is considered necessary.

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