Palbociclib

V03A - All other therapeutic products ATC L01XE33 Small molecule approved 2015 Oral First-in-class Natural product

JFDA label: Ibrance 75 mg

Mechanism of Action

Inhibitor of CDK6/cyclin D1 — CDK6/cyclin D1 inhibitor; Inhibitor of Cyclin-dependent kinase 4/cyclin D1 — Cyclin-dependent kinase 4/cyclin D1 inhibitor

Target	Action	Gene / class
CDK6/cyclin D1 efficacy	INHIBITOR
Cyclin-dependent kinase 4/cyclin D1 efficacy	INHIBITOR

Indications

Approved

Breast cancer, advanced (initial endocrine-based therapy)
Breast cancer, advanced (with disease progression following endocrine therapy)

Class profile

mechanismClass	CDK4/6 kinase inhibitor
targetMolecule	CDK4 + CDK6
targetPathway	Cell cycle G1/S checkpoint (RB pathway)
generation	1st generation CDK4/6 inhibitor
primaryTumors	HR+ HER2- Breast
resistanceMechanisms	RB1 loss,Cyclin D1 amplification,CDK6 amplification,PI3K/mTOR pathway activation,CDK4 amplification
source	NCCN/OncoKB/Goodman&Gilman13ed

Contraindications

Source: Lexicomp

Hypersensitivity to palbociclib or any component of the formulation Absolute
There are no contraindications listed in the US manufacturer's labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Common Pulmonary embolism

Nervous system disorders (3)

Very Common Fatigue · headache · peripheral neuropathy

Blood and lymphatic system disorders (6)

Very Common anemia · decreased absolute lymphocyte count · leukopenia · Neutropenia · thrombocytopenia

Common Febrile neutropenia

Gastrointestinal disorders (7)

Very Common constipation · decreased appetite · diarrhea · Nausea · stomatitis · vomiting

Common Dysgeusia

Skin and subcutaneous tissue disorders (3)

Very Common Alopecia · skin rash

Common Xeroderma

Musculoskeletal and connective tissue disorders (1)

Very Common Weakness

Eye disorders (3)

Common Blurred vision · dry eye syndrome · increased lacrimation

Infections and infestations (1)

Very Common Infection

General disorders and administration site conditions (1)

Very Common Fever

Respiratory, thoracic and mediastinal disorders (2)

Very Common epistaxis · Upper respiratory tract infection

Dosing

Source: Lexicomp

Note: Refer to aromatase inhibitor or fulvestrant monographs for respective dosing in combination with palbociclib. Breast cancer, advanced, initial endocrine-based therapy: Females (HER-2 negative): Oral: 125 mg once daily for 21 days, followed by 7 days off, repeat every 28 days (in combination with continuous aromatase inhibitor therapy); continue until disease progression or unacceptable toxicity (Finn 2015). Breast cancer, advanced (with disease progression following endocrine therapy): Females (HER-2 negative): Oral: 125 mg once daily for 21 days, followed by 7 days off, repeat every 28 days (in combination with fulvestrant [and an LHRH agonist (eg, goserelin) if pre- or perimenopausal]); continue until disease progression or unacceptable toxicity (Turner 2015). Missed/vomited doses: If a dose is vomited or missed, an additional dose should not be taken that day. Resume dosing with the next scheduled daily dose. Dosage adjustment for concomitant therapy: Strong CYP3A inhibitors: Avoid concomitant use with strong CYP3A inhibitors and consider alternatives with no or minimal CYP3A inhibition. If coadministration with a strong CYP3A inhibitor cannot be avoided, reduce palbociclib dose to 75 mg once daily. If the strong inhibitor is discontinued, increase palbociclib dose (after 3 to 5 inhibitor half-lives have elapsed) to the dose used prior to initiating the strong CYP3A inhibitor. CYP3A inducers: Avoid concomitant use with strong CYP3A inducers.

Refer to adult dosing.

CrCl >15 mL/minute: No dosage adjustment necessary. CrCl ≤15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Mild or moderate impairment (Child-Pugh classes A and B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C): Reduce dose to 75 mg once daily for 21 days, followed by 7 days off; repeat every 28 days.

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

Neutropenia was commonly observed in clinical studies, including grades 3 and 4 neutropenia. The median time to the first neutropenia episode (any grade) was 15 days; the median duration of grade 3 or higher neutropenia was 7 days. Leukopenia, anemia, lymphocytopenia, thrombocytopenia, neutropenic fever, and neutropenic sepsis have also been reported. Monitor blood counts prior to initiating therapy and at the beginning of each cycle (as well as on day 15 of the first 2 cycles), and as clinically necessary; if neutropenia is limited to grades 1 or 2 in the first 6 cycles, monitor every 3 months (prior to the beginning of a cycle) and as clinically indicated for subsequent cycles. Treatment interruption, delay, or dose reduction is recommended for grade 3 or 4 neutropenia.

GI toxicity

Nausea, vomiting, diarrhea, and stomatitis (generally grade 1 or 2) were reported from clinical studies.

Infection

Infections (including grades 3 and 4) were reported more frequently in patients receiving palbociclib and an antiestrogen compared with those receiving an antiestrogen only. Monitor for signs/symptoms of infection and manage appropriately. Disease-related concerns:

Hepatic impairment

A reduced dose is recommended in patients with severe hepatic impairment. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy & Lactation

Pregnancy

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, palbociclib may be expected to cause fetal harm if used during pregnancy. In women of reproductive potential, a pregnancy test is recommended prior to treatment initiation. Women of reproductive potential should use effective contraception during treatment and for at least 3 weeks after the last dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose. Although not approved for use in men, animal data suggests that palbociclib may affect male fertility.

Lactation

Avoid

It is not known if palbociclib is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for at least 3 weeks after the last dose.

Monitoring

Efficacy	Tumour response (RECIST criteria, tumour markers, imaging); progression-free survival; performance status (ECOG/Karnofsky)
Toxicity	CBC with differential (nadir timing depends on agent); LFTs; renal function; ECG (QT for relevant agents); echocardiogram for cardiotoxic agents (anthracyclines, trastuzumab); cumulative dose tracking for dose-limited toxicities
Clinical pearl	Treatment response is assessed after 2–3 cycles. Grade 3–4 toxicities typically require dose reduction or interruption per protocol-defined criteria.
Counseling	Attend all scheduled blood tests and imaging appointments. Report fever > 38°C (risk of neutropaenic sepsis — medical emergency), unusual bleeding, or new pain immediately.

Chemistry & Properties

Formula	C24H29N7O2
Molecular weight	447.54 g/mol
IUPAC name	6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyrido[2,3-d]pyrimidin-7-one
CAS	571190-30-2
PubChem CID	5330286
InChIKey	`AHJRHEGDXFFMBM-UHFFFAOYSA-N`
logP	2.97 (XLogP 1.8)
Polar surface area	105.04 Å²
H-bond acceptors / donors	9 / 2
Drug-likeness (QED)	0.58
Lipinski violations	0

SMILES

CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.694 h
Volume of distribution	10.339 L/kg
Protein binding	80.6%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP1A2	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
cyclin dependent kinase 4 (CDK4)	Inhibitor	pIC50 8.0
cyclin dependent kinase 6 (CDK6)	Inhibitor	pIC50 8.0

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Amprenavir	major
Apalutamide	major
Atazanavir	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Berotralstat	major
Boceprevir	major
Carbamazepine	major
Ceritinib	major
Certolizumab pegol	major
Cladribine	major
Clarithromycin	major
Clozapine	major
Cobicistat	major
Conivaptan	major
Deferiprone	major
Delavirdine	major
Enzalutamide	major
Etanercept	major
Fingolimod	major
Fosamprenavir	major
Fosphenytoin	major
Golimumab	major
Idelalisib	major
Indinavir	major
Infliximab	major
Itraconazole	major
Ketoconazole	major
Leflunomide	major
Lemborexant	major
Lonafarnib	major
Lumacaftor	major
Measles virus vaccine live attenuated	major
Mitotane	major
Mumps virus strain B level jeryl lynn live antigen	major
Natalizumab	major
Nefazodone	major
Nelfinavir	major
Ozanimod	major

Showing 40 of 100+.

Registered Products (12)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Chinasi	Capsule Palbociclib 100 mg	21 cap	MS Pharma Jordan	—
Chinasi	Capsule Palbociclib 125 mg	21 cap	MS Pharma Jordan	—
Chinasi	Capsule Palbociclib 75 mg	21 cap	MS Pharma Jordan	—
Ibrance	Capsule 75 mg	21 cap pack varies	Petra Drug Store	—
Ibrance	Capsule 100 mg	21 cap pack varies	Petra Drug Store	—
Ibrance	Capsule 125 mg	21 cap pack varies	Petra Drug Store	—
Ibrance	Tablet 75 mg	21 tab pack varies	Petra Drug Store	—
Ibrance	Tablet 100 mg	21 tab pack varies	Petra Drug Store	—
Ibrance	Tablet 125 mg	21 tab pack varies	Petra Drug Store	—
Papillio	Capsule 100 mg	21 cap	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Papillio	Capsule 75 mg	21 cap	HIKMA PHARMACEUTICALS - JORDAN	—
Papillio	Capsule 125 mg	21 cap	Hikma Pharmaceuticals Co.Ltd/Jordan	—