Palbociclib

Palbociclib Uses, Dosage, Side Effects, Food Interaction and all others data.

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.

Palbociclib is an oral, reversible, selective, small-molecule inhibitor of CDK4 and CDK6. CDK4 and CDK6 along with their regulatory partner cyclin D1 play a key role in regulating the G1- to S-phase cell-cycle transition via regulation of phosphorylation of the retinoblastoma (Rb) protein.

Due to its mechanism of action, palbociclib inhibits cell growth and suppresses DNA replication in retinoblastoma tumor suppressor gene (RB) proficient cancer cells. As expected, these RB cells present a significant increase in the proportion of cells in G1 state and the presence of palbociclib produces effective dephosphorylation of RB, reduce proliferation and induce senescence causing cell-cycle arrest.

In vitro studies showed the potential for palbociclib to reduce cellular proliferation of estrogen receptor-positive breast cancer cell lines through the inhibition of the cell-cycle progression from G1 to S phase. In this study, it was demonstrated that the sensitivity of the cells significantly increased with the expression of RB1 and CCND1 and low expression of CDKN2A. As well, palbociclib, combined with antiestrogens, enhanced in vivo antitumor activity in estrogen receptor-positive breast cancer mouse models.

In clinical trials, palbociclib, in combination with letrozole, was shown to significantly increase the progression-free survival (PFS) in patients with metastatic breast cancer without prior endocrine treatment. In the results, the PFS increased from 4.5 to 9.5 months with an overall response rate (ORR) of 24.6%.

Palbociclib
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Palbociclib
Availability	Prescription only
Generic	Palbociclib
Palbociclib Other Names	Palbociclib
Related Drugs	Arimidex, Ibrance, Femara, Aromasin, Faslodex, Verzenio, Afinitor, tamoxifen, Xeloda, Herceptin
Weight	100mg, 125mg, 75mg, 100mg, 125mg, 75mg
Type	Oral capsule, oral tablet
Formula	C₂₄H₂₉N₇O₂
Weight	Average: 447.5328 Monoisotopic: 447.238273207
Protein binding	Binding of palbociclib to human plasma proteins in vitro accounts for approximately 85% of the administered dose.
Groups	Approved, Investigational
Therapeutic Class	Targeted Cancer Therapy
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Palbociclib is a kinase inhibitor used for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:

An aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or
Fulvestrant in women with disease progression following endocrine therapy.

Palbociclib is also used to associated treatment for these conditions: Advanced Breast Cancer, Metastatic Breast Cancer, Refractory, advanced Breast cancer, Refractory, metastatic Breast cancer

How Palbociclib works

Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor that acts by binding to the ATP pocket with an IC50 in the range of 9-15 nmol/L. It is important to consider that it presents low to absent activity against other kinases.

The CDK4/6 kinase is involved, with coregulatory partner cyclin D, in the G1-S transition. Hence, inhibition of this step prevents cell cycle progression in cells in whose this pathway is functioning. This step includes the pathways of the phosphorylation of retinoblastoma protein and the E2F family of transcription factors.

Dosage

Palbociclib dosage

Palbociclib capsules are taken orally with food in combination with an aromatase inhibitor or fulvestrant.

Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment.
Dosing interruption and/or dose reductions are recommended based on individual safety and tolerability.

Side Effects

Most common adverse reactions (incidence ≥10%) were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea, thrombocytopenia, rash, vomiting, decreased appetite, asthenia, and pyrexia.

Toxicity

The reported oral Ld50 is of 100 mg/kg. In cases of overdosage, only supportive measures are considered.

Palbociclib was showed to present clastogenic activities in in vitro and in vivo assays. As well, it has been reported to produce fetal harm due to its mechanism of action. Lastly, it was shown to increase the incidence of microglial cell tumors in the central nervous system at high doses.

Precaution

Neutropenia: Monitor complete blood count prior to start of Palbociclib therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated.

Embryo-Fetal Toxicity: Palbociclib can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.

Interaction

CYP3A Inhibitors: Avoid concurrent use of Palbociclib with strong CYP3A inhibitors. If the strong inhibitor cannot be avoided, reduce the Palbociclib dose.

CYP3A Inducers: Avoid concurrent use of Palbociclib with strong CYP3A inducers.

CYP3A Substrates: The dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced when given concurrently with Palbociclib.

Food Interaction

Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of palbociclib, which may increase its serum concentration.
Avoid St. John's Wort. This herb induces the CYP3A metabolism of palbociclib and may reduce its serum concentration.
Take at the same time every day. This applies to both palbociclib capsules and tablets.
Take with food. Palbociclib capsules should be taken with food. Some subjects have reduced bioavailability of palbociclib when in a fasted state, therefore taking with food makes the bioavailability more consistent.
Take with or without food. Palbociclib tablets may be taken with or without food.

[Moderate] ADJUST DOSING INTERVAL: Administration with food may enhance the oral bioavailability of palbociclib in some patients and reduce the intersubject variability of palbociclib exposure.

According to the product labeling, palbociclib absorption and exposure were very low in approximately 13% of the population when taken in the fasted state.

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.

Compared to palbociclib given under overnight fasted conditions, the population average palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 38% and 21%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively); by 27% and 12%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories; 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively); and by 24% and 13%, respectively, when given with moderate-fat, standard calorie food (approximately 500 to 700 calories; 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) one hour before and two hours after palbociclib dosing.

GENERALLY AVOID: Grapefruit juice may increase the systemic exposure to palbociclib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Increased exposure to palbociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis.

MANAGEMENT: Patients should take palbociclib with food and avoid consumption of grapefruit or grapefruit juice during treatment.

Palbociclib Drug Interaction

Moderate: paclitaxel protein-bound, zafirlukast, diltiazem, denosumabUnknown: pancrelipase, fulvestrant, letrozole, loperamide, furosemide, gabapentin, acetaminophen, desvenlafaxine, vitamin a topical, levothyroxine, acetaminophen, liraglutide, cyanocobalamin, pyridoxine, cholecalciferol, ondansetron

Palbociclib Disease Interaction

Moderate: lung toxicity, hepatic impairment, neutropenia, premenopausal, renal impairment

Volume of Distribution

The mean apparent distribution of palbociclib is 2583 L which suggests that palbociclib penetrates extensively into peripheral tissues.

Elimination Route

Palbociclib presents a linear pharmacokinetic profile and its peak plasma concentration was observed 6-12 hours after oral administration. The oral bioavailability is reported to be of 46% with a steady-state reached after 8 days and a median accumulation ratio of 2.4.

The absorption of palbociclib is significantly reduced under fasting conditions and hence, food intake is recommended when this drug is administered.

Half Life

The mean plasma elimination half-life of palbociclib is 29 hours.

Clearance

The mean apparent oral clearance of palbociclib is of 63.1 L/h.

Elimination Route

The main route of elimination of palbociclib is through feces after hepatic metabolism while renal clearance seems to play a minor role accounting only for 17.5% of the eliminated dose.