PALBOCARE 125

Indications

• Locally advanced non-small cell lung cancer (NSCLC) with EGFR mutations
• Metastatic breast cancer, hormone receptor-positive, HER2-negative

Dosage

Adults: 75 mg once daily for 21 consecutive days of a 28-day cycle, with adjustments based on tolerance and co-administration of CYP3A4 inhibitors.

Mechanism of action

Palbociclib acts by binding to the ATP pocket of CDK4/6 with an IC50 in the range of 9-15 nmol/L. This inhibition prevents the phosphorylation of the retinoblastoma protein (RB), leading to cell cycle arrest in the G1 phase. The inhibition of this transition is crucial in cancer cells where the RB pathway is intact, resulting in reduced cellular proliferation and increased senescence.

Pharmacodynamics

Palbociclib inhibits cell growth and suppresses DNA replication in retinoblastoma proficient cancer cells. It leads to dephosphorylation of RB, resulting in decreased proliferation and induction of senescence. In preclinical studies, palbociclib demonstrated enhanced antitumor activity when combined with antiestrogens, significantly improving progression-free survival in patients with estrogen receptor-positive breast cancer.

Pharmacokinetics

Palbociclib is well absorbed, with its pharmacokinetics influenced by CYP3A4 metabolism. It has a half-life that permits once-daily dosing. The drug's exposure may be significantly affected by co-administration with CYP3A4 inhibitors or inducers, necessitating dose adjustments in such cases. It is primarily eliminated via hepatic metabolism, and no specific data is available regarding its behavior in patients with severe hepatic impairment.

Adverse effects

• diarrhoea
• eyelid pruritus
• nail discolouration
• increased risk of infection
• skin inflammation
• Stevens-Johnson syndrome
• decreased leucocytes
• neutropenia
• thrombocytopenia

Interactions

• grapefruit juice (severe - increases exposure)
• St. John's wort (severe - decreases exposure)
• ciclosporin (moderate - increases exposure)
• ergotamine (moderate - increases exposure)
• everolimus (moderate - increases exposure)
• opioids (moderate - increases exposure)
• alfentanil (moderate - increases exposure)
• fentanyl (moderate - increases exposure)
• pimozide (moderate - increases exposure)
• sirolimus (moderate - increases exposure)

Precautions

• Monitor ECG and electrolytes periodically in patients with risk factors for QTc interval prolongation
• Assess hepatic function before treatment
• Avoid in patients with severe hepatic impairment
• Use effective, non-hormonal contraception during and for 2 months after treatment in women, and 4 months after treatment in men

Pregnancy

Manufacturer advises to avoid unless essential due to toxicity in animal studies.

Breast-feeding

Manufacturer advises to avoid as it may be present in milk based on animal studies.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablet 75 mg
• Tablet 100 mg

Mechanism of action

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.

Pharmacodynamics

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%.