Pirtobrutinib

Pirtobrutinib is a moderate inhibitor of CYP2C8. Pirtobrutinib increased the AUC and C_max of repaglinide (a substrate of CYP2C8) by 130% and 98%, respectively. Therefore, since pirtobrutinib can increase the plasma concentrations of CYP2C8 substrates, caution is advised when co-administering with CYP2C8 substrates (e.g. repaglinide, dasabuvir, selexipag, rosiglitazone, pioglitazone, and montelukast).

Pirtobrutinib is a moderate inhibitor of BCRP. Pirtobrutinib increased the AUC and C_max of rosuvastatin (a BCRP substrate) by 140% and 146%, respectively. Therefore, since pirtobrutinib can increase the plasma concentrations of BCRP substrates, caution is advised when co-administering BCRP substrates (e.g. rosuvastatin). If co-administration with narrow therapeutic index BCRP substrates (e.g. high dose methotrexate, mitoxantrone) cannot be avoided, close clinical monitoring should be considered.

Patients receiving anticoagulant or antiplatelet agents may be at increased risk of haemorrhage. The risks and benefits of anticoagulant or antiplatelet therapy should be considered when co-administered with pirtobrutinib and consider additional monitoring for signs of bleeding. The use of pirtobrutinib has not been studied with warfarin or other vitamin K antagonists. Dose interruption may be required for Grade 3 or 4 bleeding events.

Pirtobrutinib is a weak inhibitor of CYP2C19. Pirtobrutinib increased the AUC and C_max of omeprazole (a CYP2C19 substrate) by 56% and 49%, respectively. Therefore, pirtobrutinib can increase the plasma concentrations of CYP2C19 substrates. If co-administration with narrow therapeutic index CYP2C19 substrates (e.g phenobarbital and mephenytoin) cannot be avoided, close clinical monitoring should be considered.

Pirtobrutinib is a weak inhibitor of CYP3A. Pirtobrutinib increased the AUC and C_max of orally administered midazolam (sensitive CYP3A substrate) by 70% and 58%, respectively. Pirtobrutinib did not have a clinically meaningful effect on the exposure of intravenously administered midazolam. Therefore, pirtobrutinib can increase the plasma concentrations of CYP3A substrates. If co-administration with narrow therapeutic index CYP3A substrates (e.g alfentanil, midazolam, tacrolimus) cannot be avoided, close clinical monitoring should be considered.

Pirtobrutinib is a weak inhibitor of P-gp. Pirtobrutinib increased the AUC and C_max of digoxin (a P-gp substrate) by 35% and 55%, respectively. Therefore, pirtobrutinib can increase the plasma concentrations of P-gp substrates. If co-administration with narrow therapeutic index P-gp substrates (e.g dabigatran etexilate and digoxin) cannot be avoided, close clinical monitoring should be considered.

In a clinical study, rifampin, a strong CYP3A inducer, decreased the AUC and C_max of pirtobrutinib by 71% and 42%, respectively. Though this decrease in pirtobrutinib exposure is not expected to be clinically meaningful, if possible avoid strong CYP3A inducers (e.g. rifampicin, carbamazepine, phenytoin).

The benefit-risk of withholding pirtobrutinib for 3 to 5 days pre- and post-surgery should be considered depending upon the type of surgery and risk of bleeding.

There are no data from the use of pirtobrutinib in pregnant women. Studies in animals have shown reproductive toxicity. Pirtobrutinib should not be used during pregnancy.

It is unknown whether pirtobrutinib is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with pirtobrutinib and for one week after the last dose of pirtobrutinib.

Women of childbearing potential/Contraception in males and females

Based on findings in animals and the genotoxicity of pirtobrutinib, pirtobrutinib can cause foetal harm when administered to a pregnant woman. Women of childbearing potential should use an effective method of contraception during treatment and for 5 weeks after the last dose of pirtobrutinib. Men are advised to use an effective method of contraception and not father a child during treatment and for 3 months after the last dose of pirtobrutinib.

Fertility

There are no data on the effect of pirtobrutinib on human fertility.

Pirtobrutinib has a minor influence on the ability to drive and use machines. Fatigue, dizziness, and asthenia have been reported in some patients during treatment with pirtobrutinib and should be considered when assessing a patient’s ability to drive or operate machines.

Summary of the safety profile

The most common adverse reactions of any grade are: fatigue (26.3%), neutropenia (22.8%), diarrhoea (22.1%) and contusion (19.0%).

The most common severe (Grade ≥ 3) adverse reactions are: neutropenia (19.7%), anaemia (7.9%) and thrombocytopenia (6.6%).

The frequency of treatment discontinuation due to adverse reactions is 1.2% and the frequency of dose reductions due to adverse reactions is 3.3%. The most common adverse reactions (reported in more than 2 patients) leading to dose reduction are neutropenia (1.8%), fatigue (0.4%), thrombocytopenia (0.3%), anaemia (0.3%) and rash (0.3%). The most common adverse reactions (reported in more than 2 patients) leading to dose discontinuation are neutropenia (0.4%) and pneumonia (0.3%).

Serious adverse reactions associated with pirtobrutinib have occurred in 11.3% of patients and the most common serious adverse reactions (occurring in ≥1% of patients) were pneumonia (4.7%), neutropenia (2.2%), anaemia (1.7%) and urinary tract infection (1.0%).

Fatal adverse reactions have been observed in 0.3% of patients (2 patients) for pneumonia and in 0.1% of patients (1 patient) for haemorrhage.

Tabulated list of adverse reactions

The table below lists the adverse drug reactions (ADRs) associated with pirtobrutinib used as a monotherapy from clinical study data. The ADRs are based on pooled data from 583 patients treated with pirtobrutinib monotherapy 200 mg QD starting dose with no dose escalation in a phase ½ clinical study. Patients were treated for MCL, chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and other non-Hodgkin lymphoma (NHL). Patients were exposed to pirtobrutinib for a median duration of 8 months. ADRs are listed below by MedDRA body system organ class. Frequency groups are defined by the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

ADRs of patients treated with pirtobrutinib monotherapy^a at 200 mg QD:

^a Frequencies are derived from pirtobrutinib exposure in patients with B-cell malignancies
^b Includes multiple adverse reaction terms
^c Severity grade assignment based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0