Palbociclib
CDK 4 and CDK 6 inhibitor in hormone sensitive breast cancer
Palbociclib is the first approved inhibitor of the cyclin dependent kinases 4 and 6 (CDK 4/6). Pfizer launched the compound on the EU market in 2016 under the brand name Ibrance. The approval covers women with locally advanced or metastatic hormone receptor positive, HER2 negative breast cancer, in combination with an aromatase inhibitor (anastrozole, letrozole, exemestane) in the first line or with fulvestrant in later therapy. Related CDK 4/6 inhibitors are ribociclib (Kisqali) and abemaciclib (Verzenios), which have partly identical and partly different indications.
The pivotal PALOMA 1, 2 and 3 trials showed a doubling of progression free survival with palbociclib compared with endocrine monotherapy. The compound has lastingly changed the first line treatment of metastatic hormone sensitive breast cancer. While the clinical benefit is substantial, therapy requires close management of neutropenia and other haematological side effects.
Mechanism of Action
The cell cycle is regulated by a sequence of kinases. CDK 4 and CDK 6 form complexes with cyclin D that phosphorylate the retinoblastoma protein (Rb). Phosphorylated Rb releases the transcription factor E2F, which initiates the transition from the G1 to the S phase. This step is decisive for DNA replication and cell division. Hormone receptor positive breast cancer cells are particularly dependent on CDK 4/6 activity.
Palbociclib binds selectively and with high affinity to CDK 4 and CDK 6 in cyclin D complexes and blocks their kinase activity. The result is arrest of the tumour cells in the G1 phase and a halt in cell proliferation. When combined with endocrine therapy (aromatase inhibitor, fulvestrant) the signalling cascade is interrupted at two levels: hormonal stimulation at the receptor level and intracellular cell cycle blockade. This explains the synergistic effect.
After oral intake palbociclib is rapidly absorbed; maximum plasma levels are reached 6 to 12 hours later. The half life is about 29 hours, allowing once daily dosing. Metabolism is predominantly hepatic via CYP3A4 and SULT2A1, with elimination via bile and faeces.
Indications
- First line therapy of locally advanced or metastatic HR+ HER2 negative breast cancer in postmenopausal women and in men, in combination with an aromatase inhibitor
- Combination with fulvestrant in patients with progression after prior endocrine therapy
- Premenopausal patients in combination with ovarian suppression (GnRH analogue such as leuprorelin or goserelin) plus aromatase inhibitor or fulvestrant
Ribociclib is additionally approved for use in younger, premenopausal patients. Abemaciclib has an additional approval in the adjuvant therapy of high risk early breast cancer. The choice of the specific CDK 4/6 inhibitor depends on indication, side effect profile and individual tolerability.
Dosage and Administration
Standard dose: 125 mg once daily orally on days 1 to 21, followed by 7 days of rest. Each cycle lasts 28 days. The dose is taken at the same time of day with a meal to optimise absorption. Capsules are swallowed whole with liquid. Tablets are also available as a film coated form that can be taken without a meal.
The combination with the endocrine partner (letrozole, anastrozole, exemestane, fulvestrant) follows each product's own instructions. Therapy continues until disease progression or intolerable side effects. Dose adjustments to 100 mg or 75 mg are common for haematological toxicity and are well studied.
Renal impairment: no dose adjustment for mild to moderate impairment; for severe impairment without dialysis no adjustment is required because of the low renal elimination. Hepatic impairment: no adjustment for mild impairment, 100 mg for moderate and 75 mg for severe impairment. Elderly patients: no mandatory adjustment.
Side Effects
Very common: neutropenia (mainly grade 3 and 4, in up to 66 percent of patients), fatigue, nausea, stomatitis, alopecia, anaemia, infections, leukopenia, diarrhoea, reduced appetite, skin rash.
Common: elevated liver enzymes, thrombocytopenia, taste changes, fever, lymphopenia, nail changes, dry skin.
Uncommon to rare but important: febrile neutropenia with infection, venous thromboembolism, interstitial lung disease and pneumonitis, QT prolongation (less than with ribociclib), severe skin reactions.
Neutropenia management: neutropenia on palbociclib is usually reversible and occurs in the first cycles. Unlike chemotherapy induced neutropenia, the infection risk at equally low neutrophil counts is lower with CDK 4/6 inhibitors. Dose adjustments and postponement of the cycle start at neutrophils below 1.0 x 10^9 per litre are standard. G CSF substitution is rarely necessary.
Interactions
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice): marked increase in palbociclib plasma levels, avoid the combination where possible or reduce the dose to 75 mg
- Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): marked reduction of plasma levels, combination not recommended
- Moderate CYP3A4 modulators: caution, clinical relevance variable
- Sensitive CYP3A substrates (midazolam, fentanyl, sirolimus, tacrolimus): palbociclib itself inhibits CYP3A, so plasma levels of these substrates may rise
- Live vaccines: avoid during therapy, the immune response may be attenuated
- Proton pump inhibitors: reduce palbociclib exposure when taken fasting; taking with a meal eliminates the effect
Special Notes
Monitoring: full blood count with differential before therapy, on day 14 of the first and second cycles, and then at the start of each subsequent cycle. Liver values every 2 weeks during the first two cycles, then by cycle. With progressive hepatic toxicity adjust or pause the dose. If pneumonitis is suspected perform a chest CT and lung function test, and discontinue therapy in case of a clinically relevant lung reaction.
Pregnancy: palbociclib is contraindicated; preclinical studies show teratogenicity. Women of childbearing potential must use effective contraception and continue it for at least 3 weeks after the end of therapy. Male patients are advised to use contraception in their partnership. Breastfeeding: not recommended, passage into breast milk has not been quantified.
Fertility: patients of childbearing potential should be informed before therapy about fertility preservation measures such as oocyte cryopreservation. In premenopausal women ovarian suppression is necessary, which temporarily eliminates fertility.
Signs of infection: patients should immediately inform their treating physician about fever, severe shortness of breath, cough and other signs of infection. The combination of neutropenia and endocrine therapy requires attention, especially during the first three cycles.
Treatment goal: palbociclib significantly prolongs progression free survival; the effect on overall survival varies between studies. Patients and clinicians should jointly weigh realistic treatment goals against the burden of side effects.
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Frequently Asked Questions
Why the pause after 21 days?
The seven day pause after 21 days of intake allows the bone marrow to regenerate, especially neutrophil granulocytes. Neutropenia is the most common dose limiting side effect, and the pause is essential for continuing therapy over many cycles. The 3 week on and 1 week off schedule has proved optimal in clinical trials.
Is the neutropenia dangerous?
The neutropenia on palbociclib differs in its risk profile from chemotherapy induced neutropenias. At equally low neutrophil counts the infection risk is considerably lower. Regular blood count checks are nevertheless important, and at neutrophils below 1.0 x 10^9 per litre dose adjustments or cycle postponements are standard. Fever should be assessed medically without delay.
Palbociclib, ribociclib or abemaciclib?
All three are effective CDK 4/6 inhibitors. Efficacy is similar, but the side effect profiles differ: palbociclib and ribociclib have pronounced neutropenia, while abemaciclib causes more gastrointestinal complaints and less neutropenia but more venous thromboembolism. Ribociclib also carries a QT prolongation risk, and abemaciclib has approval in adjuvant therapy. The choice is made individually.
Can I drink grapefruit juice?
No. Grapefruit juice is a strong inhibitor of CYP3A4, the main metabolic pathway of palbociclib. Concurrent intake raises plasma levels significantly, which intensifies side effects. Avoid grapefruit entirely during therapy. Bitter oranges can have similar effects.
Sources
- EMA, Ibrance (Palbociclib) EPAR
- AWMF, S3 Guideline Breast Cancer
- Gelbe Liste, Palbociclib active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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