Palvored Mechanism of Action

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors. ATC code: L01XE33.
Pharmacology: Pharmacodynamics: Mechanism of action: Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of multiple signalling pathways which lead to cellular proliferation.
Pharmacodynamic effects: Through inhibition of CDK4/6, palbociclib reduced cellular proliferation by blocking progression of the cell from G1 into S phase of the cell cycle. Use of palbociclib in a panel of molecularly profiled breast cancer cell lines revealed high activity against luminal breast cancers, particularly ER-positive breast cancers. In the cell lines, the loss of retinoblastoma (Rb) was associated with loss of palbociclib activity. However, further data with fresh tumour samples, no relation between RB1 expression and tumour response was observed. Similarly, no relation was observed when studying the response to palbociclib in models with patient-derived xenografts (PDX models).
Cardiac electrophysiology: Palbociclib did not prolong the QTc to any clinically relevant extent at the recommended dose of 125 mg daily (Schedule 3/1).
Pharmacokinetics: Absorption: The mean Cmax of palbociclib is generally observed between 6 to 12 hours following oral administration. The mean absolute bioavailability of palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the area under the curve (AUC) and Cmax increase proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulates with a median accumulation ratio of 2.4.
Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the population under the fasted condition. 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 AUCinf and Cmax of palbociclib increased by 21% and 38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 13% and 24% when moderate-fat food was given 1 hour before and 2 hours after palbociclib dosing. In addition, food intake significantly reduced the intersubject and intrasubject variability of palbociclib exposure. Based on these results, palbociclib should be taken with food.
Distribution: Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentration dependence. The mean fraction unbound (fu) of palbociclib in human plasma increased incrementally with worsening hepatic function. There was no obvious trend in the mean palbociclib fu in human plasma in vivo with worsening renal function. The uptake of palbociclib into human hepatocytes occurred mainly via passive diffusion. Palbociclib is not a substrate of OATP1B1 or OATP1B3.
Biotransformation: Data indicate that palbociclib undergoes extensive hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, the major primary metabolic pathways for palbociclib involved oxidation and sulphonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma.
The majority of the material was excreted as metabolites. In faeces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 25.8% of the administered dose. Data with human hepatocytes, liver cytosolic and S9 fractions, and recombinant sulphotransferase (SULT) enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.
Elimination: The geometric mean apparent oral clearance (CL/F) of palbociclib was 63 L/h, and the mean plasma elimination half-life was 28.8 hours in patients with advanced breast cancer. When given a single oral dose of [14C]palbociclib, a median of 92% of the total administered radioactive dose was recovered in 15 days; faeces (74% of dose) was the major route of excretion, with 17% of the dose recovered in urine. Excretion of unchanged palbociclib in faeces and urine was 2% and 7% of the administered dose, respectively.
Palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.
Data indicate that palbociclib has low potential to inhibit the activities of organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1, OATP1B3, and bile salt export pump (BSEP) at clinically relevant concentrations.
Special populations: Age, gender, and body weight: Gender had no effect on the exposure of palbociclib, and age and body weight had no clinically important effect on the exposure of palbociclib.
Paediatric population: Pharmacokinetics of palbociclib has not been evaluated in patients <18 years of age.
Hepatic impairment: Data indicate that palbociclib unbound exposure (unbound AUCinf) decreased by 17% in patients with mild hepatic impairment (Child-Pugh class A), and increased by 34% and 77% in patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively. Peak palbociclib unbound exposure (unbound Cmax) was increased by 7%, 38% and 72% for mild, moderate and severe hepatic impairment, respectively. In addition, mild hepatic impairment had no effect on the pharmacokinetics of palbociclib.
Renal impairment: Data indicate that total palbociclib exposure (AUCinf) increased by 39%, 42%, and 31% with mild (60 mL/min ≤CrCl <90 mL/min), moderate (30 mL/min ≤CrCl <60 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively. Peak palbociclib exposure (Cmax) was increased by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively. In addition, mild and moderate renal impairment had no effect on the pharmacokinetics of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients requiring haemodialysis.
Ethnicity: Based on an analysis of the cumulative pharmacokinetic, safety, and efficacy data across Asian and non-Asian populations, no dose adjustment based on Asian race is considered necessary.