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2015年2月3日,美国FDA以加速批准途径批准辉瑞公司Ibrance（palbociclib）用于治疗晚期（转移性）乳腺癌。
乳腺癌是美国第2大常见癌症，起源于乳腺组织并进行性发展，可转移至周围正常组织。根据美国国家癌症研究所（NCI）的估计，2014年美国约有232670名女性诊断为乳腺癌，40000名女性因此丧生。
Palbociclib可抑制与癌症细胞增殖相关的细胞周期激酶CDK4和CDK6，与来曲唑联用用于治疗尚未接受过激素疗法的绝经后ER阳性HER2阴性的转移性乳腺癌患者。
FDA 药物评估与研究中心血液和肿瘤药物办公室主任Richard Pazdur教授称，palbociclib和来曲唑联用可为转移性乳腺癌患者提供一个新的治疗选择，FDA是基于加速批准通道授予其上市许可。Ibrance曾获得FDA授予的突破性治疗药物资格，也获得了优先审评资格。此次获得FDA的加速批准，比PDUFA预定的2015年4月13日的审批期限提前了2个月。
Ibrance的疗效在165例未经治疗的绝经后ER阳性HER2阴性晚期乳腺癌患者中得到了证实。临床研究中患者被随机分配至Ibrance+来曲唑联合治疗组或letrozole单药治疗组。Ibrance+来曲唑治疗组无进展生存期（PFS）为22.2个月，来曲唑单药组为10.2个月。总生存期数据尚未获得。
最常见的药物副作用包括中性粒细胞减少、白细胞减少症、疲劳、贫血、上呼吸道感染、恶心呕吐、口腔黏膜炎症性口炎、脱发、腹泻、血小板减少、食欲下降、无力、周围神经损伤以及鼻出血等。医疗保健人员应告知患者这些风险。
药物的起始治疗剂量为125mg，持续21天，随后停止服药7天。医疗保健人员应根据患者临床表现，在开始治疗前、每个治疗周期开始前以及在前2个周期的第14天监测全血细胞计数。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use IBRANCE safely and effectively. See full prescribing information for IBRANCE.
IBRANCE ® (palbociclib) capsules, for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
IBRANCE is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. (1) This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. (14)
DOSAGE AND ADMINISTRATION
IBRANCE capsules are taken orally with food in combination with letrozole. (2)
Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment. (2.1)
Dosing interruption and/or dose reductions are recommended based on individual safety and tolerability. (2.2)
DOSAGE FORMS AND STRENGTHS
Capsules: 125 mg, 100 mg, and 75 mg (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
Hematologic: Neutropenia may occur. Monitor complete blood count prior to start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. (5.1)
Infections: Monitor for signs and symptoms and withhold dosing as appropriate. (5.2)
Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥10%) were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
CYP3A Inhibitors: Avoid concurrent use of IBRANCE with strong CYP3A inhibitors. If the strong inhibitor cannot be avoided, reduce the IBRANCE dose. (2.2, 7.1)
CYP3A Inducers: Avoid concurrent use of IBRANCE with strong and moderate CYP3A inducers. (7.2)
CYP3A Substrates: The dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced when given concurrently with IBRANCE. (7.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 2/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.
This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food [see Clinical Pharmacology (12.3)] in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. Patients should be encouraged to take their dose at approximately the same time each day.
If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.
2.2 Dose Modification
Dose modification of IBRANCE is recommended based on individual safety and tolerability [see Warnings and Precautions (5)].
Management of some adverse reactions [see Warnings and Precautions(5)]may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2 and 3 [see Warnings and Precautions (5), Adverse Reactions (6) and Clinical Studies (14)].
Table 1. Recommended Dose Modification for Adverse Reactions
| Dose Level |
Dose |
|
|
| Recommended starting dose |
125 mg/day |
| First dose reduction |
100 mg/day |
| Second dose reduction |
75 mg/day* | Table 2. Dose Modification and Management* – Hematologic Toxicities
| CTCAE Grade |
Dose Modifications |
| Grading according to CTCAE Version 4.0. |
| ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. |
|
|
| Grade 1 or 2 |
No dose adjustment is required. |
| Grade 3† |
No dose adjustment is required.
Consider repeating complete blood count monitoring one week later. Withhold initiation of next cycle until recovery to Grade ≤2. |
| Grade 3 ANC (<1000 to 500/mm3) + Fever ≥38.5ºC and/or infection |
Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2 (≥1000/mm3).
Resume at next lower dose. |
| Grade 4† |
Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2.
Resume at next lower dose. | Table 3. Dose Modification and Management – Non-Hematologic Toxicities
| CTCAE Grade |
Dose Modifications |
| Grading according to CTCAE Version 4.0. |
| CTCAE=Common Terminology Criteria for Adverse Events. |
| Grade 1 or 2 |
No dose adjustment is required. |
| Grade ≥3 non-hematologic toxicity (if persisting despite medical treatment) |
Withhold until symptoms resolve to:
- Grade ≤1;
- Grade ≤2 (if not considered a safety risk for the patient)
|
|
Resume at the next lower dose. | See manufacturer's prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.
Dose Modifications for Use With Strong CYP3A Inhibitors
Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink "Pfizer" on the cap, "PBC 125" on the body.
100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink "Pfizer" on the cap, "PBC 100" on the body.
75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink "Pfizer" on the cap, "PBC 75" on the body.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Neutropenia
Decreased neutrophil counts have been observed in clinical trials with IBRANCE. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in the randomized clinical trial (Study 1). Median time to first episode of any grade neutropenia per laboratory data was 15 days (13–117 days). Median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions (6.1)].
Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration (2.2)].
5.2 Infections
Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate.
5.3 Pulmonary Embolism
Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate.
5.4 Embryo-Fetal Toxicity
Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm. IBRANCE caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with IBRANCE and for at least two weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
6 ADVERSE REACTIONS
The following topics are described below and elsewhere in the labeling:
Neutropenia [see Warnings and Precautions (5.1)]
Infections [see Warnings and Precautions (5.2)]
Pulmonary Embolism [see Warnings and Precautions (5.3)]
6.1 Clinical Studies Experience
Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months.
Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1.
Permanent discontinuation due to an adverse reaction occurred in 7 of 83 (8%) patients receiving IBRANCE plus letrozole and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%).
The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.
The most frequently reported serious adverse reactions in patients receiving IBRANCE plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).
An increase incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia [see Dosage and Administration (2.2)].
Adverse drug reactions (≥10%) reported in patients who received IBRANCE plus letrozole or letrozole alone in Study 1 are listed in Table 4.
Table 4. Adverse Reactions* (≥10%) in Study 1
| IBRANCE + Letrozole (N=83) |
Letrozole Alone (N=77) |
| System Organ Class |
All Grades |
Grade 3 |
Grade 4 |
All Grades |
Grade 3 |
Grade 4 |
| Adverse Reaction |
% |
% |
% |
% |
% |
% |
| Grading according to CTCAE Version 3.0. |
| CTCAE=Common Terminology Criteria for Adverse Events; N=number of subjects; N/A=not applicable; URI=Upper respiratory infection. |
|
|
| Infections and infestations |
| URI† |
31 |
1 |
0 |
18 |
0 |
0 |
| Blood and lymphatic system disorders |
| Neutropenia |
75 |
48 |
6 |
5 |
1 |
0 |
| Leukopenia |
43 |
19 |
0 |
3 |
0 |
0 |
| Anemia |
35 |
5 |
1 |
7 |
1 |
0 |
| Thrombocytopenia |
17 |
2 |
0 |
1 |
0 |
0 |
| Metabolism and nutrition disorders |
| Decreased appetite |
16 |
1 |
0 |
7 |
0 |
0 |
| Nervous system disorders |
| Peripheral neuropathy‡ |
13 |
0 |
0 |
5 |
0 |
0 |
| Respiratory, thoracic and mediastinal disorders |
| Epistaxis |
11 |
0 |
0 |
1 |
0 |
0 |
| Gastrointestinal disorders |
| Stomatitis§ |
25 |
0 |
0 |
7 |
1 |
0 |
| Nausea |
25 |
2 |
0 |
13 |
1 |
0 |
| Diarrhea |
21 |
4 |
0 |
10 |
0 |
0 |
| Vomiting |
15 |
0 |
0 |
4 |
1 |
0 |
| Skin and subcutaneous tissue disorders |
| Alopecia |
22¶ |
N/A |
N/A |
3# |
N/A |
N/A |
| General disorders and administration site conditions |
| Fatigue |
41 |
2 |
2 |
23 |
1 |
0 |
| Asthenia |
13 |
2 |
0 |
4 |
0 |
0 | Table 5. Laboratory Abnormalities for Patients in Study 1
| IBRANCE + Letrozole (N=83) |
Letrozole Alone (N=77) |
| Laboratory Abnormality |
All Grades
% |
Grade 3
% |
Grade 4
% |
All Grades
% |
Grade 3
% |
Grade 4
% |
| N=number of patients. |
| White blood cells decreased |
95 |
44 |
0 |
26 |
0 |
0 |
| Neutrophils decreased |
94 |
57 |
5 |
17 |
3 |
0 |
| Lymphocytes decreased |
81 |
17 |
1 |
35 |
3 |
0 |
| Hemoglobin decreased |
83 |
5 |
1 |
40 |
3 |
0 |
| Platelets decreased |
61 |
3 |
0 |
16 |
3 |
0 | 7 DRUG INTERACTIONS
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a time-dependent inhibitor of CYP3A.
7.1 Agents That May Increase Palbociclib Plasma Concentrations
Effect of CYP3A Inhibitors
Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment. If coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
7.2 Agents That May Decrease Palbociclib Plasma Concentrations
Effect of CYP3A Inducers
Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John's Wort) [see Clinical Pharmacology (12.3)].
Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of IBRANCE. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) [see Clinical Pharmacology (12.3)].
7.3 Drugs That May Have Their Plasma Concentrations Altered by Palbociclib
Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies.
Data
Animal Data
In a fertility and early embryonic development study in female rats, palbociclib was administered orally for 15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure (AUC) at the recommended dose.
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses up to 300 mg/kg/day and 20 mg/kg/day palbociclib, respectively, during the period of organogenesis. The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights. At doses ≥100 mg/kg/day in rats, there was an increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra). At the maternally toxic dose of 20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small phalanges in the forelimb. At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic exposures were approximately 4 and 9 times the human exposure (AUC) at the recommended dose.
CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation Day 14.5 until birth) due to severe anemia. However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition.
8.2 Lactation
Risk Summary
There are no data on the presence of palbociclib in human milk, the effects of IBRANCE on the breastfed child, or the effects of IBRANCE on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, advise a nursing woman to discontinue breastfeeding during treatment with IBRANCE.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Use in Specific Populations (8.1)].
Infertility
Males
Based on findings in animals, male fertility may be compromised by treatment with IBRANCE [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].
8.4 Pediatric Use
The safety and efficacy of IBRANCE in pediatric patients have not been studied.
8.5 Geriatric Use
Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were ≥65 years of age and 8 patients (10%) were ≥75 years of age. No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.
8.6 Hepatic Impairment
Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)].
8.7 Renal Impairment
Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures.
11 DESCRIPTION
IBRANCE capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase inhibitor. The molecular formula for palbociclib is C24H29N7O2. The molecular weight is 447.54 daltons. The chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, and its structural formula is:
Palbociclib is a yellow to orange powder with pKa of 7.4 (the secondary piperazine nitrogen) and 3.9 (the pyridine nitrogen). At or below pH 4, palbociclib behaves as a high-solubility compound. Above pH 4, the solubility of the drug substance reduces significantly.
Inactive ingredients: Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells. The light orange, light orange/caramel and caramel opaque capsule shells contain gelatin, red iron oxide, yellow iron oxide, and titanium dioxide; and the printing ink contains shellac, titanium dioxide, ammonium hydroxide, propylene glycol and simethicone.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma protein (Rb) phosphorylation resulting in reduced E2F expression and signaling and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens leads to increased cell senescence, which was sustained for up to 6 days following drug removal. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling and tumor growth compared to each drug alone.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of palbociclib on the QTc interval was evaluated in 184 patients with advanced cancer. No large change (i.e., >20 ms) in the QTc interval was detected at the mean observed maximal steady-state palbociclib concentration following a therapeutic schedule (e.g., 125 mg daily for 21 consecutive days followed by 7 days off to comprise a complete cycle of 28 days).
12.3 Pharmacokinetics
The pharmacokinetics of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects.
Absorption
The mean Cmax of palbociclib is generally observed between 6 to 12 hours (time to reach maximum concentration, Tmax) following oral administration. 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: 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 IBRANCE with food. Compared to IBRANCE given under overnight fasted conditions, the population average AUCinf and Cmax of palbociclib increased by 21% and 38%, respectively, when given 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), by 12% and 27%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories with 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively), and by 13% and 24%, respectively, when moderate-fat, standard calorie food (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) was given one hour before and two hours after IBRANCE dosing.
Distribution
Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The geometric mean apparent volume of distribution (Vz/F) was 2583 L (26% CV).
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 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%). The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.
Elimination
The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) 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.
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), gender had no effect on the exposure of palbociclib, and age and body weight had no clinically important effect on the exposure of palbociclib.
Pediatric Population
Pharmacokinetics of IBRANCE have not been evaluated in patients <18 years of age.
Drug Interactions
In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the metabolism of palbociclib. Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady state in humans. In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.
CYP3A Inhibitors: Data from a drug interaction trial in healthy subjects (N=12) indicate that coadministration of multiple 200 mg daily doses of itraconazole with a single 125 mg IBRANCE dose increased palbociclib AUCinf and the Cmax by approximately 87% and 34%, respectively, relative to a single 125 mg IBRANCE dose given alone.
CYP3A Inducers: Data from a drug interaction trial in healthy subjects (N=14) indicate that coadministration of multiple 600 mg daily doses of rifampin with a single 125 mg IBRANCE dose decreased palbociclib AUCinf and the Cmax by 85% and 70%, respectively, relative to a single 125 mg IBRANCE dose given alone.
CYP3A Substrates: Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady state in humans. In a drug interaction trial in healthy subjects (N=26), coadministration of midazolam with multiple doses of IBRANCE increased the midazolam AUCinf and the Cmax values by 61% and 37%, respectively, as compared with administration of midazolam alone.
Gastric pH Elevating Medications: In a drug interaction trial in healthy subjects, coadministration of a single 125 mg dose of IBRANCE with multiple doses of the proton pump inhibitors (PPI) rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease), when compared to a single dose of IBRANCE 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 dose of IBRANCE with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared to a single dose of IBRANCE administered alone.
Letrozole: Data from a drug interaction trial in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the two drugs were coadministered.
Effect of Palbociclib on Transporters: In vitro evaluations indicated that palbociclib has a low potential to inhibit the activities of drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2 and organic anion transporting polypeptide (OATP)1B1, OATP1B3 at clinically relevant concentrations.
Effect of Transporters on Palbociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of palbociclib at therapeutic doses.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with palbociclib.
Palbociclib was clastogenic in an in vitro micronucleus assay in Chinese Hamster Ovary cells and in vivo in the bone marrow of male rats that received doses ≥100 mg/kg/day for three weeks. Clastogenicity occurred via an aneugenic mechanism. Palbociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and did not induce structural chromosomal aberrations in the in vitro human lymphocyte chromosome aberration assay.
In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to 300 mg/kg/day (approximately 4 times human clinical exposure based on AUC) and no adverse effects were observed in the female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the rat and 3 mg/kg/day in the dog (approximately 6 times and similar to human exposure (AUC), at the recommended dose, respectively). Male fertility studies with palbociclib have not been conducted; however, in repeat-dose toxicity studies, testicular degeneration was observed in rats and dogs at 30 and 0.2 mg/kg/day, respectively (approximately 11 and 0.1 times human exposure (AUC), at the recommended dose, respectively), which was partially reversible in the rat and dog following a 12-week non-dosing period.
13.2 Animal Toxicology and/or Pharmacology
Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), teeth (degeneration/necrosis of ameloblasts in actively growing teeth), kidney (tubule vacuolation, chronic progressive nephropathy), and adipose tissue (atrophy) were identified in the 27-week repeat-dose toxicology study in rats and were most prevalent in males at doses ≥30 mg/kg/day (approximately 11 times the human exposure (AUC) at the recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present in the 15-week repeat-dose toxicology study in rats, but with lower incidence and severity. The rats used in these studies were approximately 7 weeks old at the beginning of the studies. Altered glucose metabolism or associated changes in pancreas, eye, teeth, kidney, and adipose tissue were not identified in dogs in repeat-dose toxicology studies up to 39 weeks duration.
14 CLINICAL STUDIES
Study 1 was a randomized, open-label, multicenter study of IBRANCE plus letrozole versus letrozole alone conducted in postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their advanced disease. A total of 165 patients were randomized in Study 1. 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). IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Patients received study treatment until progressive disease, unmanageable toxicity, or consent withdrawal.
Patients enrolled in this study had a median age of 63 years (range 38 to 89). The majority of patients were Caucasian (90%) and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Forty-three percent of patients had received chemotherapy and 33% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of advanced breast cancer. Forty-nine percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease. Nineteen percent of patients had bone only disease and 48% of patients had visceral disease.
The major efficacy outcome measure of the study was investigator-assessed PFS evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST). Major efficacy results from Study 1 are summarized in Table 6 and Figure 1. Consistent results were observed across patient subgroups of, disease-free interval, disease site and prior therapy. The treatment effect of the combination on PFS was also supported by a retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.621 (95% CI: 0.378, 1.019). Overall response rate in patients with measurable disease as assessed by the investigator was higher in the IBRANCE plus letrozole compared to the letrozole alone arm (55.4% versus 39.4%). At the time of the final analysis of PFS, overall survival (OS) data was not mature with 37% of events.
Table 6. Efficacy Results – Study 1 (Investigator Assessment, Intent-to-Treat Population)
IBRANCE + Letrozole
(N=84) |
Letrozole
(N=81) |
| CI=confidence interval; N=number of patients. |
| Progression-Free Survival (PFS) |
|
|
| Number of PFS Events (%) |
41 (48.8%) |
59 (72.8%) |
| Hazard ratio (95% CI) |
0.488 (0.319, 0.748) |
| Median PFS [months] (95% CI) |
20.2 (13.8, 27.5) |
10.2 (5.7, 12.6) | Figure 1. Kaplan-Meier Curves of Progression-Free Survival – Study 1 (Investigator Assessment, Intent-to-Treat Population)
16 HOW SUPPLIED/STORAGE AND HANDLING
IBRANCE is supplied in the following strengths and package configurations:
IBRANCE Capsules
| Package Configuration |
Capsule Strength (mg) |
NDC |
Capsule Description |
| Bottles of 21 capsules |
125 |
NDC 0069-0189-21 |
opaque, hard gelatin capsules, size 0, with caramel cap and body, printed with white ink "Pfizer" on the cap, "PBC 125" on the body |
| Bottles of 21 capsules |
100 |
NDC 0069-0188-21 |
opaque, hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink "Pfizer" on the cap, "PBC 100" on the body |
| Bottles of 21 capsules |
75 |
NDC 0069-0187-21 |
opaque, hard gelatin capsules, size 2, with light orange cap and body, printed with white ink "Pfizer" on the cap, "PBC 75" on the body | Store at 20°C to 25°C(68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). |
