IBRANCE Palbociclib 125mg Capsule 1's

There is no known antidote for Palbociclib. The treatment of Palbociclib (Ibrance) overdose should consist of general supportive measures.

 

 

Effects on Fertility: Palbociclib did not affect estrous cycling, mating or fertility in female rats at any dose tested up to 300 mg/kg/day (approximately 3 times human clinical exposure based on AUC). However, no clinical data have been obtained on fertility in human females. Based on nonclinical safety findings, male fertility may be compromised by treatment with Palbociclib (Ibrance). Men should consider sperm preservation prior to beginning therapy with Palbociclib (Ibrance).
Palbociclib is considered to have the potential to impair reproductive function and fertility in male humans based on nonclinical findings in rats and dogs. Palbociclib-related findings in the testis, epididymis, prostate and seminal vesicle included decreased organ weight, atrophy or degeneration, hypospermia, intratubular cellular debris, lower sperm motility and density, and decreased secretion. These findings were observed in rats and/or dogs at exposures ≥6 times or subtherapeutic compared to human clinical exposure based on AUC, respectively. The effects appeared to be reversible.
Use in Pregnancy: Pregnancy Category D.
There are no adequate and well-controlled studies in pregnant women receiving Palbociclib (Ibrance). Based on findings in animals and mechanism of action, Palbociclib can cause fetal harm when administered to a pregnant woman.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving Palbociclib (Ibrance). Women of childbearing potential who are receiving this drug should use adequate contraceptive methods during therapy and for at least a month after completing therapy. Partners of females of childbearing potential receiving this drug should use adequate contraception methods during therapy and for at least 14 weeks after completing therapy.
Palbociclib was fetotoxic in pregnant rats and rabbits. Reduced fetal body weights were observed at a maternally toxic dose of 300 mg/kg/day in rats (3 times human clinical exposure based on AUC) and an increased incidence of skeletal variations, including small phalanges in the forelimb, was observed at a maternally toxic dose of 20 mg/kg/day in rabbits (6 times human clinical exposure based on AUC). An increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra) at ≥100 mg/kg/day (equivalent to human clinical exposure based on AUC) was seen in rats while other skeletal variations and skeletal ossification were seen in rabbits at ≥10mg/kg/day (3 times human clinical exposure based on AUC). Actual fetal exposure and cross-placenta transfer have not been examined.
CDK4/6 double knockout mice have been reported to die in late stages of fetal development due to severe anemia. However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition.
Female patients taking Palbociclib during pregnancy or who become pregnant while taking Palbociclib should be apprised of the potential hazard to the fetus.
Use in Lactation: No studies have been conducted in humans to assess the effect of Palbociclib (Ibrance) on milk production, its presence in breast milk or its effects on the breast-fed child. It is unknown whether Palbociclib is excreted in human milk. Patients receiving Palbociclib (Ibrance) should not breast-feed.

 

Store at temperatures not exceeding 30°C.

 

PHARMACOLOGIC CATEGORY: Antineoplastic Agent (Protein kinase inhibitor).
Pharmacology: Pharmacodynamics: Through inhibition of CDK4/6, Palbociclib reduced cellular proliferation by blocking progression of the cell from G1 into S phase of the cell cycle. Testing of Palbociclib in a panel of molecularly profiled breast cancer cell lines revealed high efficacy against luminal breast cancers, particularly estrogen receptor (ER)-positive breast cancers. Mechanistic analyses revealed that the combination of Palbociclib with anti-estrogen agents enhanced the re-activation of retinoblastoma (Rb) through inhibition of Rb phosphorylation resulting in reduced E2F signalling and growth arrest.
The enhanced growth arrest of the ER-positive breast cancer cell lines treated with Palbociclib and anti-estrogen agents is accompanied by increased cell senescence resulting in a sustained cell cycle arrest following drug removal and increased cell size associated with a senescent phenotype. In vivo studies using a patient-derived ER-positive breast cancer xenograft model (HBCx-34) demonstrated that the combination of Palbociclib and letrozole further enhanced inhibition of Rb phosphorylation, downstream signalling and dose-dependent tumor growth. This supports the contribution of senescence-associated growth arrest as a mechanism associated with the antitumour efficacy of combined Palbociclib/ER antagonist in ER-positive breast cancer models.
In the presence or absence of an anti-estrogen, Palbociclib-treated bone marrow cells did not become senescent and resumed proliferation following Palbociclib withdrawal, consistent with pharmacologic quiescence. The in vitro breast cancer cells, conversely, became senescent following Palbociclib or anti-estrogen treatment with additive effects in combination and remained arrested in the presence of anti-estrogen.
Mechanism of Action: Palbociclib is a small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of multiple signaling pathways which lead to cellular proliferation.
Clinical Trials: Study A5481003: Randomized Phase 1/2 study of Palbociclib (Ibrance) in combination with letrozole (PALOMA-1): The efficacy of Palbociclib was evaluated in a randomized, open-label, multicenter study of Palbociclib plus letrozole versus letrozole alone conducted in postmenopausal women with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who did not receive previous systemic treatment for their advanced disease.
The study was comprised of a limited Phase 1 portion (N = 12), designed to confirm the safety and tolerability of the combination Palbociclib plus letrozole, followed by a randomized Phase 2 portion (N = 165), designed to evaluate the efficacy and safety of Palbociclib in combination with letrozole compared with letrozole alone in the first-line treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer. Randomization was stratified by disease site (visceral versus bone only versus other) and by disease-free interval (>12 months from the end of adjuvant treatment to disease recurrence versus ≤12 months from the end of adjuvant treatment to disease recurrence or de novo advanced disease).
The patient demographic and baseline characteristics were generally balanced between the study arms in terms of age, race, disease sites, stage and prior therapies.
The primary endpoint of the study was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. The median PFS (mPFS) for patients in the Palbociclib plus letrozole arm was 20.2 months (95% confidence interval [CI]: 13.8-27.5) and 10.2 months (95% CI: 5.7-12.6) for patients in the letrozole alone arm. The observed hazard ratio (HR) was 0.488 (95% CI: 0.319-0.748) in favor of Palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of 0.0004.
At the final overall survival (OS) analysis, the observed HR was 0.897 (95% CI: 0.623, 1.294) with a stratified 1-sided p-value of 0.2812. The median OS in the Palbociclib plus letrozole arm was 37.5 months (95% CI: 31.4, 47.8) and in the letrozole alone arm was 34.5 months (95% CI: 27.4, 42.6).
The estimated survival probabilities at 12, 24, and 36 months between the 2 treatment arms were 89.0% versus 87.0%, 77.9% versus 71.1%, and 50.8% versus 47.4%, in favor of Palbociclib plus letrozole, respectively.
Study A5481008: Randomized, Phase 3 study of Palbociclib (Ibrance) in combination with letrozole (PALOMA-2): The efficacy of Palbociclib in combination with letrozole versus letrozole plus placebo was evaluated in an international, randomized, double-blind, placebo-controlled, parallel-group, multicentre study conducted in women with ER-positive, HER2-negative locally advanced or metastatic breast cancer who had not received prior systemic treatment for their advanced disease, whose disease was not amenable to resection or radiation therapy with curative intent, and for whom chemotherapy was not clinically indicated based on investigator's best medical judgement.
A total of 666 postmenopausal women were randomized 2:1 to either the Palbociclib plus letrozole arm or to the placebo plus letrozole arm and were stratified by site of disease (visceral, non-visceral), disease-free interval from the end of (neo)adjuvant treatment to disease recurrence (de novo metastatic, ≤12 months from the end of adjuvant treatment to disease recurrence, >12 months from the end of adjuvant treatment to disease recurrence) and by the type of prior (neo)adjuvant anticancer therapies (prior hormonal therapy, no prior hormonal therapy).
Patients continued to receive their assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurred first. Crossover between treatment arms was not allowed.
Patients were well matched for baseline demographics and disease characteristics between the Palbociclib plus letrozole arm and the placebo plus letrozole arm. The median age of patients enrolled in this study was 62 years (range 28-89). A detailed summary of the demographics and baseline characteristics are presented in Table 1. (See Table 1.)

The primary endpoint of the study was PFS evaluated according to RECIST version 1.1 as assessed by investigator. Secondary efficacy endpoints included objective response (OR), duration of response (DOR), clinical benefit response (CBR), overall survival (OS), safety, EQ-5D scores and health-related quality of life (QoL) assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire.
At the data cutoff date of 26-February-2016, the study met its primary objective of improving PFS. The HR was 0.576 (95% CI: 0.463, 0.718) in favour of Palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of <0.000001.
An updated analysis of the primary and secondary endpoints was performed after an additional 15 months of follow up (data cutoff date: 31-May-2017). A total of 405 PFS events were observed; 245 events (55.2%) in the Palbociclib plus letrozole arm and 160 (72.1%) in the comparator arm.
Table 2 shows the efficacy results based on the primary and the updated analyses from the PALOMA-2 study, as assessed by the investigator and by the independent review. (See Table 2.)

The Kaplan-Meier curves for PFS based on the updated cutoff date of 31 May 2017 are displayed in Figure 1 as follows. (See Figure 1.)

Prespecified subgroup analyses indicated that the treatment effect (by median PFS) was consistent in all subgroups defined by stratification factors and baseline characteristics, including presence/absence of visceral metastases at baseline and presence of bone-only disease at baseline. An exploratory analysis showed that median PFS was longer in the Palbociclib plus letrozole arm for 512 patients whose tumor tested positive for Rb protein expression by immunohistochemistry (IHC) (HR 0.543 [95% CI: 0.433, 0.681], mPFS 27.4 months versus 13.7 months). For the 51 patients whose tumors tested negative for Rb protein expression by IHC, the difference between treatment arms was not statistically significant.
Patients with advanced, symptomatic visceral spread at risk of life-threatening complications in the short term were not included in PALOMA-2.
At the time of the updated analyses for PFS, time to initiation of subsequent anticancer therapies was also assessed. The results from these analyses are shown in Table 3. (See Table 3.)

The overall survival (OS) data were not mature at the time of the final PFS analysis (20% of patients had died). Patients will continue to be followed for the final analysis.
An analysis of time-to-deterioration composite endpoint (TTD) in Functional Assessment of Cancer Therapy-Breast (FACT-B), defined as the time between baseline and first occurrence of decrease of ≥7 points in FACT-B scores, was carried out based on survival analysis methods using a Cox proportional hazards model and log-rank test. No statistically significant difference was observed in TTD in FACT-B total scores between the Palbociclib plus letrozole arm and the placebo plus letrozole arm (HR of 1.042 [95% CI: 0.838, 1.295]; 1-sided p-value=0.663.
Pre- and perimenopausal women were not enrolled in PALOMA-1 or PALOMA-2.
Study A5481023: Randomized, Phase 3 study of Palbociclib (Ibrance) in combination with fulvestrant (PALOMA-3): The efficacy of Palbociclib in combination with fulvestrant versus placebo plus fulvestrant was evaluated in an international, randomized, double-blind, parallel-group, multicentre study conducted in women with HR-positive, HER2-negative locally advanced or metastatic breast cancer, regardless of their menopausal status, whose disease progressed after prior endocrine therapy and was not amenable to resection or radiation therapy with curative intent based on investigator's best medical judgement.
A total of 521 pre/postmenopausal women whose disease had progressed on or within 12 months after completion of adjuvant endocrine therapy or on or within 1 month from prior endocrine therapy for advanced disease were randomized 2:1 to the Palbociclib plus fulvestrant arm or the placebo plus fulvestrant arm and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus postmenopausal) and presence of visceral metastases. Crossover between treatment arms was not allowed.
Patients were balanced for baseline demographics and prognostic characteristics between the Palbociclib plus fulvestrant arm and the placebo plus fulvestrant arm. The median age of patients enrolled in this study was 57 years (range 29, 88). The majority of patients in each treatment arm were White, had documented sensitivity to prior hormonal therapy and were postmenopausal. All patients had received prior systemic therapy and most patients in each treatment arm had received a previous chemotherapy regimen. More than half (62%) had an ECOG performance status of 0, 60% had visceral metastases and 60% had received more than 1 prior hormonal regimen for their primary diagnosis. (See Table 4.)

The primary endpoint of the study was investigator-assessed PFS evaluated according to RECIST version 1.1. Secondary PFS analyses were based on a random sample Blinded Independent Central Radiology Review (BICR) of 40.5% of the ITT population. Secondary endpoints included OR, DOR, CBR, OS, safety, change in QoL and TTD. Patient-reported outcomes including Global QoL and pain were measured using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30) and the Breast Cancer Module (BR23) questionnaire.
The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysis conducted on 82% of the planned PFS events at final analysis; the results crossed the prespecified Haybittle-Peto efficacy boundary (α=0.00135), demonstrating a statistically significant prolongation in PFS and a clinically meaningful treatment effect. The estimated HR from the stratified analysis was 0.422 (95% CI: 0.318, 0.560; 1-sided p<0.000001) in favour of Palbociclib plus fulvestrant. The mPFS was 9.2 months (95% CI: 7.5-not estimable [NE]) in the Palbociclib plus fulvestrant arm and 3.8 months (95% CI: 3.5-5.5) in the placebo plus fulvestrant arm.
A more mature update of efficacy data is reported in Figure 2 and Table 5. (See Figure 2 and Table 5.)

Prolongation of PFS in the Palbociclib plus fulvestrant arm was also demonstrated in most individual patient subgroups supporting internal consistency of PFS benefit findings within the study and was supported by the secondary PFS random sample BICR audit. (See Figure 3.)

As per inclusion criteria, pre/perimenopausal women were enrolled in the study if already treated with an LHRH agonist from at least 4 weeks. If they were not treated with goserelin prior to study entry, they were switched to goserelin when they started the study treatment. In the Palbociclib plus fulvestrant arm 70 pre/perimenopausal women received goserelin for the duration of the study and in the placebo plus fulvestrant arm 36 pre/perimenopausal women received goserelin.
The Palbociclib plus fulvestrant arm demonstrated similar clinical benefit in the pre/perimenopausal patient population (HR = 0.494 [95% CI: 0.300, 0.813]) and postmenopausal population (HR = 0.508 [95% CI: 0.395, 0.652]). Similarly, the mPFS for the Palbociclib plus fulvestrant arm was 11.3 months (95% CI: 7.5, 15.0) in the pre/perimenopausal setting versus 11.2 months (95% CI: 9.5, 12.7) in the postmenopausal setting; while the mPFS in the placebo plus fulvestrant arm was 5.6 months (95% CI: 1.7, 9.2) in the pre/perimenopausal setting versus 3.9 months (95% CI: 3.5, 5.5) in the postmenopausal setting.
The overall survival (OS) data were not mature at the time of the final PFS analysis (11% of patients had died). Patients will continue to be followed for the final analysis.
Patient-reported symptoms were assessed using the EORTC QLQ-C30 and EORTC QLQ-BR23. A total of 335 patients in the Palbociclib plus fulvestrant arm and 166 patients in the placebo plus fulvestrant arm completed the questionnaire at baseline and at least 1 postbaseline visit.
Time-to-Deterioration (TTD) was prespecified as time between baseline and first occurrence of ≥10-point increase from baseline in pain symptom scores. Addition of Palbociclib to fulvestrant resulted in a symptom benefit by significantly delaying TTD in pain symptom scores compared with placebo plus fulvestrant (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85]; p<0.001).
Men were not enrolled in PALOMA-1, PALOMA-2 and PALOMA-3.
Pharmacokinetics: The pharmacokinetics (PK) of Palbociclib were characterized in patients with solid tumours including advanced breast cancer and in healthy volunteers.
Absorption: The time to C_max (T_max) of Palbociclib is generally between 6 to 12 hours following oral administration. The mean absolute bioavailability of Palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and C_max increase proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, Palbociclib accumulates with a median accumulation ratio of 2.4 (range 1.5-4.2).
Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the population under the fasted condition. Food intake increased the Palbociclib exposure in this small subset of the population, but did not alter Palbociclib exposure in the rest of the population to a clinically relevant extent. Therefore, food intake reduced the intersubject variability of Palbociclib exposure, which supports administration of Palbociclib (Ibrance) with food.
Compared to Palbociclib given under overnight fasted conditions, the AUC_inf and C_max 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 Palbociclib dosing. In addition, food intake significantly reduced the intersubject and intrasubject variability of Palbociclib exposure. Based on these results, Palbociclib should be taken with food.
Gastric pH elevating medication effect: In a healthy subject study, coadministration of a single 125 mg dose of Palbociclib with multiple doses of the proton pump inhibitor (PPI) rabeprazole under fed conditions decreased Palbociclib C_max by 41%, but had limited impact on AUC_inf (13% decrease), when compared to a single 125 mg dose of Palbociclib administered alone. Given the reduced effect on gastric pH of H2 receptor antagonists and local antacids compared to PPIs, the effect of these classes of acid-reducing agents on Palbociclib exposure under fed conditions is expected to be minimal. Under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists or local antacids on Palbociclib exposure. In another healthy subject study, coadministration of a single 125 mg dose of Palbociclib (Ibrance) with multiple doses of the PPI rabeprazole under fasted conditions decreased Palbociclib AUC_inf and C_max by 62% and 80%, respectively, when compared with a single dose of Palbociclib (Ibrance) administered alone.
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 unbound (f_u) of Palbociclib in human plasma in vivo increased incrementally with worsening hepatic function. There was no obvious trend in the mean Palbociclib f_u in human plasma in vivo with worsening renal function. The geometric mean apparent volume of distribution (V_z/F) was 2583 (26%) L.
Metabolism: In vitro and in vivo studies indicate that Palbociclib undergoes extensive 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. The major circulating metabolite was a glucuronide conjugate of Palbociclib, although it only represented 1.5% of the administered dose in the excreta. The glucuronide metabolite is primarily formed by UGT1A1 and to a lesser extent, by UGT1A4. The majority of the material was excreted as metabolites. 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/h 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. Excretion of unchanged Palbociclib in feces and urine was 2.3% and 6.9% of the administered dose, respectively.
Special Populations: Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age ranging from 22 to 89 years and body weight ranging from 37.9 to 123 kg), gender had no effect on the exposure of Palbociclib and age and body weight had no clinically important effect on the exposure of Palbociclib.
Elderly (≥65 years): Of 444 patients who received Palbociclib in Study A5481008 (PALOMA-2), 181 patients (41%) were ≥65 years of age with 133 (30%) patients between the age of 65 and 74, and 48 (11%) patients ≥75 years of age. Of 347 patients who received Palbociclib in Study A5481023 (PALOMA-3), 86 patients (25%) were ≥65 years of age with 59 (17%) patients between the age of 65 and 74, and 27 (8%) patients ≥75 years of age. No overall differences in safety were observed across all age groups and elderly age groups. Neutropenia was the most common adverse event with Palbociclib across all age groups; however, the incidence of febrile neutropenia was low in all age groups. No overall differences effectiveness of Palbociclib were observed between these patients and younger patients.
Children and Adolescents: Pharmacokinetics of Palbociclib have not been evaluated in patients ≤18 years of age.
Renal Impairment: Data from a pharmacokinetic trial in subjects with varying degrees of renal function indicate that total Palbociclib exposure (AUC_inf) 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 ≥90 mL/min) renal function. Peak Palbociclib exposure (C_max) was increased by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. This study included a small number of patients with severe renal impairment (n=6) and Palbociclib use in this population is considered largely uncharacterised.
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 haemodialysis.
Hepatic Impairment: Data from a pharmacokinetic trial in subjects with varying degrees of hepatic function indicate that Palbociclib unbound exposure (unbound AUC_inf) 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 hepatic impairment (Child-Pugh class C), respectively, relative to subjects with normal hepatic function. This study included a small number of patients with severe hepatic impairment (n=7) and Palbociclib use in this population is considered largely uncharacterised.
Peak Palbociclib unbound exposure (unbound C_max) 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 PK of Palbociclib.
Asian race: In a dedicated PK study in healthy volunteers, Palbociclib geometric mean AUC_inf and C_max values were 30% and 35% higher, respectively, in Japanese subjects compared with non-Asian subjects after a single oral dose. However, this finding was not reproduced consistently in subsequent studies in breast cancer patients after multiple dosing. Based on an analysis of the cumulative pharmacokinetic, safety and efficacy data, no dose adjustment based on Asian race is considered necessary.
Cardiac electrophysiology: The effect of Palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with breast cancer. Palbociclib did not prolong QTc to any clinically relevant extent at the recommended dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment.
Toxicology: Preclinical Safety Data: The primary target organ findings following single and/or repeat dosing included hematolymphopoietic and male reproductive organ effects in rats and dogs, and effects on bone and actively growing incisors in rats only. These systemic toxicities were generally observed at clinically relevant exposures based on AUC. Partial to full reversal of effects on the hematolymphopoietic, male reproductive systems and incisor teeth were established, whereas the bone effect was not reversed following a 12-week nondosing period. The effect on bone indicate a potential risk for children and adolescents. In addition, cardiovascular effects (QTc prolongation, decreased heart rate and increased RR interval and systolic blood pressure) were identified in telemetered dogs at ≥4 times human clinical exposure based on C_max.
Genotoxicity: Palbociclib was not mutagenic in a bacterial reverse mutation (Ames) assay and did not induce structural chromosomal aberrations in the in vitro human lymphocyte chromosome aberration assay.
Palbociclib induced micronuclei via an aneugenic mechanism in Chinese Hamster Ovary cells in vitro and in the bone marrow of rats.
Carcinogenicity: Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year rat study. Palbociclib was negative for carcinogenicity in transgenic mice at doses up to 60 mg/kg/day (No Observed Effect Level [NOEL] approximately 7 times human clinical exposure based on AUC). Palbociclib was carcinogenic in rats. Palbociclib-related neoplastic finding in rats included an increased incidence of microglial cell tumors in the central nervous system of males at 30 mg/kg/day (5 times human clinical exposure based on AUC). There were no neoplastic findings in female rats at any dose up to 200 mg/kg/day. The NOEL for Palbociclib-related carcinogenicity effects was 10 mg/kg/day (approximately 2 times the human clinical exposure based on AUC) and 200 mg/kg/day (approximately 4 times the human clinical exposure based on AUC) in males and females, respectively. The relevance of the male rat neoplastic finding to humans is unknown.