Pirtobrutinib

Pirtobrutinib is a reversible, non-covalent inhibitor of Bruton’s tyrosine kinase (BTK), a signalling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. Blocking BTK interrupts the signals that malignant B cells use to proliferate, traffic, respond to chemical attractants and adhere, as in mantle cell lymphoma and chronic lymphocytic leukaemia.

Mechanism of Action

• BTK signalling: in B cells, BTK signalling activates the pathways needed for proliferation, trafficking, chemotaxis and adhesion.
• Reversible, non-covalent binding: pirtobrutinib binds wild-type BTK and BTK carrying C481 mutations, and inhibits its kinase activity. Unlike covalent BTK inhibitors, which bind in the active site, its activity is maintained when this region carries mutations such as C481.
• Selectivity: more than 300-fold selective for BTK over 98% of other kinases tested. In nonclinical studies it inhibited BTK-mediated CD69 expression on B cells and the proliferation of malignant B cells.
• Continuous target inhibition: at 200 mg once daily, trough concentrations can exceed the BTK IC96, so BTK stays inhibited throughout the dosing interval whatever the natural rate of BTK turnover.
• Cardiac electrophysiology: a single 900 mg dose, which gives about twice the steady-state concentrations of the recommended dose, caused no change of more than 10 ms in the QTcF interval in 30 healthy subjects, and there was no relationship between exposure and QTc change.

Pharmacokinetics

• Absorption: absolute bioavailability 85.5% after a single 200 mg dose in healthy subjects; median time to peak concentration about 2 hours; absorption does not depend on pH. A high-fat, high-calorie meal lowered the peak concentration by 23% and delayed it by 1 hour but did not change AUC, so the tablets can be taken with or without food.
• Dose proportionality and steady state: exposure rises roughly in proportion to dose. Steady state is reached within 5 days of once-daily dosing, with an accumulation ratio of 1.63 (AUC). At 200 mg once daily in cancer patients the mean steady-state AUC is 97,100 h·ng/mL and Cmax 6,690 ng/mL.
• Distribution: mean apparent central volume of distribution 35.4 L in cancer patients; 96% bound to plasma proteins, independent of concentration and the same in severe renal impairment; blood-to-plasma ratio 0.79.
• Metabolism: mainly through CYP3A4, with direct glucuronidation by UGT1A8 and UGT1A9.
• Elimination: effective half-life about 19 hours and apparent clearance about 2 L/h. After a radiolabelled 200 mg dose, 57% was recovered in urine (10% as unchanged drug) and 37% in faeces (18% unchanged).
• Special populations: body weight, serum albumin and kidney function change clearance only modestly. A rise in weight from 70 to 120 kg is predicted to raise clearance by 24%, a fall in albumin from 40 to 30 g/L by 21%, and a fall in eGFR from 90 to 30 mL/min to lower it by 16%. These changes are unlikely to matter, and no dose adjustment is recommended.

• Mantle cell lymphoma (MCL): as monotherapy for adults with relapsed or refractory mantle cell lymphoma who have previously been treated with a Bruton’s tyrosine kinase (BTK) inhibitor.
• Chronic lymphocytic leukaemia (CLL): as monotherapy for adults with chronic lymphocytic leukaemia.

Jaypirca holds a conditional marketing authorisation in the EU.

• Hypersensitivity to pirtobrutinib or to any of the excipients.

The table in the SmPC is based on 1,153 patients treated with Jaypirca 200 mg once daily (median exposure 18 months) for mantle cell lymphoma, chronic lymphocytic leukaemia or small lymphocytic lymphoma, and other non-Hodgkin lymphoma. The most common adverse reactions of any grade (in at least 20% of patients) were neutropenia (27.4%) and haemorrhage (20.4%). The most common severe (grade 3 or higher) reactions were neutropenia (22.8%), anaemia (9.0%), pneumonia (8.8%) and thrombocytopenia (7.2%). Adverse reactions led to discontinuation in 3.3% of patients (most often pneumonia, 0.8%) and to dose reduction in 4.3% (most often neutropenia, 2.4%).

Very common (≥1/10): pneumonia, upper respiratory tract infection, neutropenia, anaemia, thrombocytopenia, headache, haemorrhage, bruising, contusion, diarrhoea, nausea, rash, arthralgia, fatigue.

Common (≥1/100 to <1/10): urinary tract infection, lymphocytosis, atrial fibrillation or flutter, epistaxis, haematuria, haematoma, conjunctival haemorrhage, petechiae, abdominal pain, peripheral oedema.

Not known: increased hepatic enzymes.

Haemorrhage, bruising, rash, neutropenia, anaemia, thrombocytopenia and lymphocytosis are grouped terms that each cover several reported events. Serious adverse reactions occurred in 18.0% of patients, most commonly pneumonia (8.2%), haemorrhage (2.9%), neutropenia (2.6%), anaemia (2.4%), atrial fibrillation or flutter (1.1%) and urinary tract infection (1.0%). Fatal reactions were seen with pneumonia (0.7%), haemorrhage (0.3%) and urinary tract infection (0.1%). Second primary malignancies, most often non-melanoma skin cancers, occurred commonly, and tumour lysis syndrome rarely (see Special Instructions).

Pirtobrutinib is mainly metabolised by CYP3A4, UGT1A8 and UGT1A9. It is itself a moderate inhibitor of CYP2C8 and BCRP and a weak inhibitor of P-gp, CYP2C19 and CYP3A.

• Strong CYP3A inhibitors: itraconazole raised pirtobrutinib AUC by 48% without changing peak concentration. This is not clinically meaningful, and no dose adjustment is needed.
• Strong CYP3A inducers: rifampicin lowered AUC by 71% and Cmax by 42%. The fall is not expected to be clinically meaningful, but strong inducers (for example rifampicin, carbamazepine, phenytoin) should be avoided if possible.
• Proton pump inhibitors: omeprazole made no clinically significant difference to pirtobrutinib exposure.
• CYP2C8 substrates: the AUC of repaglinide rose by 130% and its Cmax by 98%. Take care with CYP2C8 substrates such as repaglinide, dasabuvir, selexipag, rosiglitazone, pioglitazone and montelukast.
• BCRP substrates: the AUC of rosuvastatin rose by 140% and its Cmax by 146%. Take care with BCRP substrates such as rosuvastatin. If narrow-therapeutic-index BCRP substrates (for example high-dose methotrexate, mitoxantrone) cannot be avoided, close clinical monitoring should be considered.
• P-gp substrates: the AUC of digoxin rose by 35% and its Cmax by 55%. If narrow-therapeutic-index P-gp substrates (for example dabigatran etexilate, digoxin) cannot be avoided, close monitoring should be considered.
• CYP2C19 substrates: the AUC of omeprazole rose by 56% and its Cmax by 49%. If narrow-therapeutic-index CYP2C19 substrates (for example phenobarbital, mephenytoin) cannot be avoided, close monitoring should be considered.
• CYP3A substrates: a sensitive CYP3A substrate given by mouth rose by 70% in AUC and 58% in Cmax, with no clinically meaningful change when the same substrate was given intravenously. If narrow-therapeutic-index CYP3A substrates (for example alfentanil, midazolam, tacrolimus) cannot be avoided, close monitoring should be considered.
• Anticoagulants and antiplatelet agents: they may increase the risk of bleeding. Weigh the benefit and risk and consider extra monitoring for bleeding. Pirtobrutinib has not been studied with warfarin or other vitamin K antagonists.
• Food: a high-fat meal has no clinically significant effect, so the tablets can be taken with or without food.

Treatment should be started and supervised by a physician experienced in the use of anticancer therapies. The tablets are swallowed whole with a glass of water, with or without food, at about the same time each day. They must not be chewed, crushed or split.

Recommended Dose

• 200 mg once daily as monotherapy, continued until disease progression or unacceptable toxicity.

Dose Interruption

Dosing is interrupted until recovery to grade 1 or baseline for any of the following:

• Grade 3 neutropenia with fever and/or infection.
• Grade 4 neutropenia lasting 7 days or more.
• Grade 3 thrombocytopenia with bleeding.
• Grade 4 thrombocytopenia.
• Grade 3 or 4 non-haematological toxicity.

Asymptomatic lymphocytosis is not regarded as an adverse reaction, and patients should continue taking Jaypirca. In the clinical studies, adverse events in a limited number of patients were managed by dose reduction; section 4.2 of the SmPC gives no fixed reduction steps.

Special Populations

• Elderly: no dose adjustment for age.
• Renal impairment: no adjustment in mild, moderate or severe impairment; there are no data in patients on dialysis.
• Hepatic impairment: no adjustment in mild, moderate or severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed or Vomited Dose

If more than 12 hours have passed since a missed dose, take the next dose at its scheduled time and do not take an extra dose. After vomiting, do not take an additional dose; continue with the next scheduled dose.

Infections

Serious infections, including fatal cases, have occurred. The most frequent grade 3 or higher infections were pneumonia, COVID-19 pneumonia, COVID-19 and sepsis. Prophylactic antimicrobial therapy should be considered in patients at increased risk of opportunistic infections, and dose interruption may be needed depending on the grade of infection and whether neutropenia is present.

Haemorrhage

Bleeding events, including fatal cases, have occurred with and without thrombocytopenia. Major bleeding of grade 3 or higher, including gastrointestinal bleeding and intracranial haemorrhage, has been seen. Patients should be monitored for signs of bleeding, and those taking anticoagulant or antiplatelet agents may be at higher risk. Grade 3 or 4 bleeding may require dose interruption. The benefit and risk of withholding pirtobrutinib for 3 to 5 days before and after surgery should be considered, depending on the type of surgery and the bleeding risk.

Cytopenias

Grade 3 or 4 neutropenia, anaemia and thrombocytopenia have occurred. Complete blood counts should be monitored during treatment as medically indicated, and dosing interrupted according to the grade of cytopenia.

Atrial Fibrillation and Flutter

Atrial fibrillation and atrial flutter have been seen, particularly in patients with a history of atrial fibrillation and/or several cardiovascular conditions. Patients should be monitored for signs and symptoms, with an electrocardiogram as medically indicated, and dosing may need to be interrupted.

Second Primary Malignancies

Second primary malignancies have occurred commonly, most often non-melanoma skin cancers. Patients should be monitored for skin cancers and advised to protect themselves from sun exposure.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported rarely. Patients with a high tumour burden before treatment are at highest risk, so the risk should be assessed and patients monitored as clinically indicated.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: findings in animals and the genotoxicity of pirtobrutinib mean it can cause foetal harm. Women of childbearing potential should use effective contraception during treatment and for 5 weeks after the last dose. Men are advised to use effective contraception and not to father a child during treatment and for 3 months after the last dose.
• Pregnancy: there are no data in pregnant women, and animal studies showed reproductive toxicity. Jaypirca should not be used during pregnancy.
• Breastfeeding: it is unknown whether pirtobrutinib passes into human milk and a risk to the infant cannot be excluded. Breastfeeding should be stopped during treatment and for one week after the last dose.
• Fertility: there are no data on the effect on human fertility.

Lactose

The tablets contain lactose (38 mg in the 50 mg tablet and 77 mg in the 100 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.

Effect on Driving

Jaypirca has a minor influence on the ability to drive and use machines. Fatigue, dizziness and asthenia have been reported and should be considered when judging whether a patient can drive or operate machines.

Jaypirca tablets need no special storage conditions. They are supplied in blisters of polyvinylchloride/polychlorotrifluoroethylene sealed with aluminium foil.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), a medicinal product subject to restricted medical prescription, started and supervised by a physician experienced in anticancer therapy. Jaypirca is taken at home, so it is supplied to the patient or to the treating clinic on prescription.