Palbociclib

CDK4/6 inhibitors
CDK4/6 inhibitors
High alert
An error with this medicine can cause serious harm: double checks and protocols are used.
Pregnancy: avoid
Avoid in pregnancy. Can harm the fetus: a pregnancy test is done before starting, effective contraception is used during treatment and for a time afterwards (by women and by men…

The first CDK4/6 inhibitor: with hormone therapy it holds HR-positive, HER2-negative breast cancer in G1. Main effect: neutropenia.

Updated Nov 1, 2026

Also called: PD-0332991

Quick facts

Group: CDK4/6 inhibitors
Target: Cyclin-dependent kinases 4 and 6 (CDK4/6)
Used for: HR-positive · The same cancer
Key effects: Neutropenia and leukopenia · Infections · Fatigue
Monitor: Complete blood count before starting · Lung symptoms
ATC: L01EF01

No doses: the clinician sets them by the current guideline.

Mechanism of action

Cyclin-dependent kinases 4 and 6 (CDK4/6)Palbociclib

The figure shows palbociclib (PD-0332991) in the ATP pocket of human CDK6, crystallised with a viral cyclin partner.

Target in 3D: Cyclin-dependent kinases 4 and 6 (CDK4/6). PDB structure 2EUF (RCSB PDB, public domain). View the structure at RCSB PDB

Palbociclib blocks the ATP site of CDK4 and CDK6 without affecting CDK1, 2 or 5. Cyclin D–CDK4/6 can no longer phosphorylate Rb, so Rb keeps the E2F transcription factors bound and the tumour cell arrests in G1 instead of copying its DNA. Combined with an aromatase inhibitor or fulvestrant, which cut the oestrogen signal that drives cyclin D, it markedly lengthens the time before the cancer progresses.

Cyclin D–CDK4/6 phosphorylates Rb at the G1/S checkpoint
Palbociclib blocks the ATP site of CDK4 and CDK6
Rb stays active and holds E2F: the cell arrests in G1
Paired with an aromatase inhibitor or fulvestrant

Indications

HR-positive, HER2-negative advanced or metastatic breast cancer, with an aromatase inhibitor as initial endocrine therapy (postmenopausal women and men). Breast cancer →
The same cancer with fulvestrant after progression on endocrine therapy. Breast cancer →

Adverse effects

Common

Neutropenia and leukopenia
Infections
Fatigue, nausea, diarrhoea, decreased appetite
Mouth sores (stomatitis)
Hair thinning, dry skin, rash; anaemia and thrombocytopenia

Contraindications

No absolute contraindications in the label apart from hypersensitivity; see the warnings

Key interactions

Strong CYP3A4 inhibitors (clarithromycin, itraconazole, ketoconazole, ritonavir) and grapefruit: Raise palbociclib exposure markedly; the combination is avoided or the dose is lowered.
Strong CYP3A inducers (rifampicin, phenytoin, carbamazepine, enzalutamide, St John's wort): Lower palbociclib levels; they are avoided.
Narrow-margin CYP3A substrates (midazolam, ciclosporin, tacrolimus, sirolimus, everolimus, fentanyl, ergotamine): Palbociclib raises their levels.

What is monitored

Complete blood count before starting and during treatment
Signs of infection
Lung symptoms (cough, breathlessness)

Administration and safety

Oral; swallowed whole, never split, crushed, chewed or opened.
Given in cycles with a rest week in each cycle; capsules with food, tablets with or without food.
Grapefruit, its juice and St John's wort are avoided because they change its levels.

Pregnancy and breastfeeding

Avoid in pregnancy. Can harm the fetus: a pregnancy test is done before starting, effective contraception is used during treatment and for a time afterwards (by women and by men with partners who could conceive), and breastfeeding is avoided.

Nursing care

Review the neutrophil count, as ordered, before treatment continues.
Teach to report fever, chills or other signs of infection at once.
Mouth care and soft diet for stomatitis; report nosebleeds or easy bruising.
Confirm a negative pregnancy test before the first dose and teach contraception during treatment and afterwards.

Pharmacokinetics

Absorption: Oral; capsules are taken with food, tablets with or without food.
Metabolism: Liver, CYP3A and the sulfotransferase SULT2A1; it also inhibits CYP3A.
Half-life: About 29 hours.

Test yourself

Think of the answer, then tap the question to see it.

At which point of the cell cycle does palbociclib stop tumour cells?

At the G1 to S transition, by keeping Rb unphosphorylated.

Which drugs is palbociclib combined with in breast cancer?

An aromatase inhibitor (such as letrozole) or fulvestrant.

Which blood test is followed during palbociclib treatment?

The complete blood count, because neutropenia is its main toxicity.

Add to my cards (3)

Connections

← Back to the class: CDK4/6 inhibitors

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Palbociclib: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2024); Palbociclib - NCI (National Cancer Institute, 2024); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.