Palbociclib

Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases 4 and 6. It binds the ATP pocket of the kinases (IC50 about 9–15 nmol/L) and has little or no activity against other kinases. Cyclin D1 and CDK4/6 lie downstream of many signalling pathways that drive cell proliferation, and they control the passage of a cell from G1 into S phase.

Mechanism of Action

• Cell-cycle control: CDK4 and CDK6, together with cyclin D, phosphorylate the retinoblastoma protein (Rb) so that E2F transcription factors can switch on genes needed for DNA replication.
• Inhibition: palbociclib blocks progression from G1 into S phase and so reduces cell proliferation. In Rb-proficient cells it lowers Rb phosphorylation and causes cell-cycle arrest with features of senescence.
• Tumour sensitivity: activity was highest in luminal breast cancer cell lines, particularly oestrogen receptor-positive ones. In cell lines, loss of Rb was linked to loss of activity, but in tumour samples and patient-derived xenograft models no relation between RB1 expression and response was seen.
• With anti-oestrogens: in mouse models of oestrogen receptor-positive breast cancer, combining palbociclib with an anti-oestrogen enhanced antitumour activity.
• Cardiac electrophysiology: at 125 mg daily there was no clinically relevant QTc prolongation.

Pharmacokinetics

• Absorption: peak concentrations are reached 6 to 12 hours after a dose; absolute bioavailability is 46% at 125 mg. Exposure rises in proportion to dose from 25 to 225 mg, steady state is reached within 8 days, and the median accumulation ratio is 2.4. With the capsules, about 13% of people absorb very little drug when fasted; food raises exposure in them and reduces variability in everyone, so the capsules are taken with food. The film-coated tablets may be taken with or without food.
• Distribution: about 85% bound to plasma proteins in vitro, with no concentration dependence. The apparent volume of distribution is about 2,583 L, indicating wide tissue distribution.
• Metabolism: extensive hepatic metabolism, mainly by CYP3A and the sulphotransferase SULT2A1, through oxidation and sulphonation, with acylation and glucuronidation as minor routes. Unchanged palbociclib is the main circulating compound; the sulphamic acid conjugate is the main component in faeces.
• Elimination: apparent oral clearance about 63 L/h and mean half-life about 29 hours. Of a radiolabelled dose, 74% was recovered in faeces and 17% in urine; unchanged drug accounted for only 2% (faeces) and 7% (urine).
• Special populations: sex, age and body weight have no clinically important effect. Unbound exposure fell by 17% in mild hepatic impairment and rose by 34% and 77% in moderate and severe impairment. Total exposure rose by 31–42% across mild to severe renal impairment. Exposure was higher in Japanese volunteers after a single dose, but this was not consistent after repeated dosing, and no adjustment for Asian race is needed.

Palbociclib is indicated for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer:

• In combination with an aromatase inhibitor.
• In combination with fulvestrant, in women who have received prior endocrine therapy.

In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

• Hypersensitivity to palbociclib or to any of the excipients.
• Use of preparations containing St John’s wort.

The safety profile comes from 872 patients treated with palbociclib plus letrozole (527) or fulvestrant (345). The most common reactions (≥20%) were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia. The most common grade 3 or higher reactions (≥2%) were neutropenia, leukopenia, infections, anaemia, increased AST, fatigue and increased ALT. Dose reductions or modifications for an adverse reaction occurred in 38.4% of patients, and permanent discontinuation in 5.2%.

Very common (≥1/10): infections, neutropenia, leukopenia, anaemia, thrombocytopenia, decreased appetite, stomatitis, nausea, diarrhoea, vomiting, rash, alopecia, dry skin, fatigue, asthenia, pyrexia, increased ALT, increased AST.

Common (≥1/100 to <1/10): febrile neutropenia, dysgeusia, blurred vision, increased lacrimation, dry eye, venous thromboembolism, epistaxis, interstitial lung disease or pneumonitis, palmar-plantar erythrodysaesthesia syndrome, increased blood creatinine.

Uncommon (≥1/1,000 to <1/100): cutaneous lupus erythematosus, erythema multiforme.

Neutropenia of any grade occurred in 82.1% of patients (grade 3 in 57.3%, grade 4 in 11.1%), with a median time to the first episode of 15 days and a median duration of 7 days at grade 3 or higher. Febrile neutropenia was reported in about 2% of patients. Severe, life-threatening or fatal interstitial lung disease or pneumonitis can occur, as can venous thromboembolism and serious infections.

Palbociclib is metabolised mainly by CYP3A and SULT2A1, and it is itself a weak, time-dependent inhibitor of CYP3A.

• Strong CYP3A inhibitors (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, grapefruit and grapefruit juice): avoid. Itraconazole raised palbociclib exposure (AUC) by 87%. If the combination is unavoidable, reduce palbociclib to 75 mg once daily, and return to the previous dose after 3 to 5 half-lives of the inhibitor once it is stopped. Mild and moderate CYP3A inhibitors need no dose change.
• Strong CYP3A inducers (carbamazepine, enzalutamide, phenytoin, rifampicin, St John’s wort): avoid, because exposure may fall and efficacy be lost; rifampicin cut exposure (AUC) by 85%. St John’s wort is contraindicated. Moderate inducers such as modafinil (exposure down by 32%) need no dose change.
• Acid-reducing medicines: a proton pump inhibitor reduced exposure to the capsules by 62% when taken fasted, but only slightly (13%) with a meal, which is why the capsules are taken with food. H2-receptor antagonists and local antacids are not expected to matter when taken with food.
• CYP3A substrates with a narrow therapeutic index (for example ciclosporin, dihydroergotamine, ergotamine, everolimus, quinidine, sirolimus, tacrolimus): palbociclib raised midazolam exposure by 61%, so their doses may need reducing.
• Transporter substrates: in vitro, palbociclib may inhibit P-glycoprotein (for example digoxin, dabigatran, colchicine), BCRP (for example pravastatin, rosuvastatin, fluvastatin, sulfasalazine) and OCT1 (for example metformin), which could increase their effects.
• Statins: statins that are CYP3A4 or BCRP substrates may raise the risk of rhabdomyolysis; fatal cases have been reported with simvastatin or atorvastatin.
• Endocrine partners: no interaction with letrozole, fulvestrant or tamoxifen. Interaction studies with oral contraceptives have not been done.

Treatment is started and supervised by a physician experienced in the use of anticancer medicines. Palbociclib is taken by mouth at about the same time each day. The hard capsules are taken with food, preferably a meal; the film-coated tablets may be taken with or without food. Both are swallowed whole: capsules must not be chewed, crushed or opened, tablets must not be chewed, crushed or split, and a broken or cracked capsule or tablet must not be taken. Palbociclib must not be taken with grapefruit or grapefruit juice.

Recommended Dose

• 125 mg once daily for 21 consecutive days, followed by 7 days off treatment (Schedule 3/1), making a 28-day cycle. Treatment continues for as long as the patient benefits, or until unacceptable toxicity.
• With an aromatase inhibitor: dosed as in its own SmPC. Pre- or perimenopausal women must also have an LHRH agonist.
• With fulvestrant: 500 mg intramuscularly on days 1, 15 and 29, then monthly. Pre- or perimenopausal women are treated with an LHRH agonist throughout.

Dose Adjustments

• Dose levels: 125 mg/day, then 100 mg/day, then 75 mg/day. If a reduction below 75 mg/day is needed, treatment is stopped.
• Blood counts: checked before starting, at the start of each cycle and on day 15 of the first two cycles, and as indicated. If neutropenia stays at grade 1 or 2 during the first six cycles, counts are checked every three months before a cycle. Starting a cycle needs a neutrophil count of at least 1,000/mm³ and platelets of at least 50,000/mm³.
• Haematological toxicity: no change for grade 1 or 2. In grade 3, withhold on day 1 of a cycle until grade 2 or less, recheck counts within a week, and restart at the same dose (consider a lower dose after recovery taking more than a week, or recurrence on day 1 of later cycles); on day 15 of the first two cycles, continue the current dose and repeat the count on day 22. In grade 3 neutropenia with fever of 38.5 °C or more or infection, or in grade 4, withhold until grade 2 or less and resume at the next lower dose.
• Non-haematological toxicity: for persisting grade 3 or higher events, withhold until grade 1 (or grade 2 if no safety risk), then resume at the next lower dose.
• Interstitial lung disease or pneumonitis: stop permanently if severe.

Special Populations

• Elderly: no dose adjustment at 65 years or older.
• Hepatic impairment: no adjustment in mild or moderate impairment (Child-Pugh A or B); in severe impairment (Child-Pugh C), 75 mg once daily on the 3/1 schedule.
• Renal impairment: no adjustment in mild, moderate or severe impairment (creatinine clearance of 15 mL/min or more); data are insufficient for haemodialysis.
• Children and adolescents: breast cancer has no relevant use in children, and efficacy below 18 years has not been demonstrated.

Missed or Vomited Dose

Do not take an extra dose that day. Take the next dose at the usual time.

Pre- and Perimenopausal Women

Ovarian ablation or suppression with an LHRH agonist is mandatory when palbociclib is combined with an aromatase inhibitor. The fulvestrant combination has been studied in these women only with an LHRH agonist.

Neutropenia and Infections

Dose interruption, reduction or delayed cycles are recommended for grade 3 or 4 neutropenia. Because palbociclib suppresses the bone marrow, infections occurred more often than with the comparators (grade 3 in 5.6% and grade 4 in 0.9%). Patients are monitored for signs of infection and should report any fever promptly.

Lung Disease and Thromboembolism

Interstitial lung disease or pneumonitis occurred in 1.4% of patients in clinical studies, and fatal cases have been reported since marketing. Patients are monitored for hypoxia, cough and dyspnoea; if new or worsening respiratory symptoms appear, interrupt treatment and evaluate. Venous thromboembolic events have been reported, so patients are monitored for deep vein thrombosis and pulmonary embolism.

Other Precautions

• Critical visceral disease: efficacy and safety have not been studied.
• Hepatic or renal impairment: use with caution and close monitoring when impairment is moderate or severe.
• CYP3A inhibitors and inducers: avoid strong inhibitors and inducers, as described under Drug Interactions.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential, or their male partners, must use adequate, highly effective contraception during treatment and for at least 3 weeks (women) or 14 weeks (men) after the last dose.
• Pregnancy: data are limited or absent, and animal studies showed reproductive toxicity. Palbociclib is not recommended in pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: it is unknown whether it passes into human milk; patients should not breastfeed.
• Fertility: rat fertility was unaffected, but findings in male reproductive organs suggest male fertility may be compromised, and men may consider sperm preservation before treatment. There are no human data.

Excipients with Known Effect

The capsules contain lactose (56 mg, 74 mg or 93 mg per capsule), so patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them; the tablets contain no lactose. Each capsule contains less than 1 mmol (23 mg) of sodium.

Effect on Driving

Palbociclib has a minor influence on the ability to drive and use machines. It may cause fatigue, so patients should take care.

The capsules need no special storage conditions. They are supplied in blister strips (cartons of 21 or 63 capsules) or in a bottle of 21 capsules; not all pack sizes may be marketed. The film-coated tablets need no special temperature conditions but should be kept in the original blister package to protect them from moisture.

Hard capsules: 4 years. Film-coated tablets: 3 years. Do not use after the expiry date.

Prescription only (Rx), started and supervised by a physician experienced in anticancer treatment. Palbociclib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.