Pirtobrutinib Oral

Mantle Cell Lymphoma

Pirtobrutinib is used for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 lines of prior systemic therapy, including an inhibitor of Bruton's tyrosine kinase (BTK).^[1][3] This indication is approved under accelerated approval based on response rate.^[1][5][6] Continued FDA approval may be contingent on confirmation of clinical benefit in additional trials.^[1][5] Pirtobrutinib has been designated an orphan drug by FDA for the treatment of MCL.^[2]

Clinical Experience

Efficacy of pirtobrutinib in the treatment of MCL is based principally on the results of an open-label, single-arm study (BRUIN) in 120 patients.^[1][3] Patients received a median of 3 prior lines of therapy (range: 1-9), with 93% having received 2 or more prior treatments.^[1] All patients received 1 or more prior lines of therapy containing a BTK inhibitor; other prior therapies included chemoimmunotherapy in 88%, hematopoietic stem cell transplant (HSCT) in 20%, lenalidomide in 18%, and chimeric antigen receptor (CAR) T-cell therapy in 9%.^[1] The most commonly received prior BTK inhibitors were ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%).^[1] Some patients received more than one prior BTK inhibitor; the last BTK inhibitor was discontinued for refractory or progressive disease, toxicity, or other reasons in 83, 10, or 5% of patients, respectively.^[1] Patients with active CNS lymphoma or who had received HSCT or CAR T-cell therapy within 60 days were excluded.^[1] The median age of patients enrolled in the study was 71 years (range: 46-88 years); 79% of patients were male and 78% were white.^[1] The variant of MCL was classic/leukemic, pleomorphic, or blastoid in 78, 12, or 11% of patients, respectively.^[1] The simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) score was low, intermediate, or high in 15, 59, or 26% of patients, respectively.^[1]

Patients received pirtobrutinib 200 mg orally once daily until disease progression or unacceptable toxicity occurred.^[1][3] Efficacy was based on overall response rate and duration of response, as assessed by an independent review committee using 2014 Lugano criteria.^[1][3] At an estimated median follow-up of 7.3 months, the investigator-assessed overall response rate in pirtobrutinib-treated patients was 50%; 13% of patients receiving the drug had achieved a complete response.^[1] At the time of data analysis, the median time to response and duration of response were 1.8 and 8.3 months, respectively.^[1][3] Following initiation of single-agent pirtobrutinib therapy, lymphocytosis (i.e., absolute lymphocyte count >=5000/mm³ and an increase of at least 50% from baseline) occurred in 34% of patients.^[1] The median time to onset of lymphocytosis was 1.1 weeks, with 75% of cases occurring within 2.1 weeks.^[1] The median duration of lymphocytosis was 11 weeks.^[1]

Clinical Perspective

Clinical practice guidelines from European experts provide recommendations for the treatment of MCL, an uncommon type of B-cell non-Hodgkin lymphoma.^[13] Therapy is dependent on staging and/or age at time of diagnosis.^[13] In early disease, radiotherapy with conventional chemotherapy can be used in a small percentage of patients with small tumor burden.^[13] For more advanced disease or in the presence of high tumor burden, immunochemotherapy (e.g., rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is recommended, with a dose-intensified regimen for patients <=65 years of age and conventional dosing for patients >65 years, followed by autologous stem cell transplantation (<=65 years only) plus rituximab maintenance therapy.^[13] For patients with relapsed disease, immunochemotherapy or targeted therapies with BTK inhibitors or lenalidomide are recommended.^[13]

Pirtobrutinib can re-establish BTK inhibition in patients previously treated with a covalent (irreversible) BTK inhibitor, thus extending the benefit of targeting the BTK pathway.^[3][6][9] Whether pirtobrutinib can improve clinical outcomes more than other currently available BTK inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib) remains to be established.^[6] A phase 3 trial comparing pirtobrutinib to other available BTK inhibitors in patients with MCL who have received at least 1 prior line of therapy (but not a BTK inhibitor) is ongoing.^[5][6][9]

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Pirtobrutinib is used for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults who have received at least 2 prior lines of systemic therapy, including a BTK inhibitor and a B-cell chronic lymphoma 2 (BCL-2) inhibitor (e.g., venetoclax).^[1][3][7] This indication is approved under accelerated approval based on response rate.^[1] Continued FDA approval for this indication may be contingent on confirmation of clinical benefit in additional trials.^[1] Pirtobrutinib has been designated an orphan drug by FDA for this use.^[2]

Clinical Experience

Efficacy of pirtobrutinib in the treatment of CLL and SLL is based principally on results from an open-label, single-arm, multicohort study (BRUIN) in which 108 patients with CLL/SLL who were previously treated with at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor, were treated with pirtobrutinib.^[1][3][7] Patients with active CNS involvement by lymphoma or who had received allogeneic HSCT within 60 days were excluded.^[1] Patients had a median age of 68 years (range: 41-88 years); baseline ECOG performance status was 0 or 1 in 91% of patients, and 48% of patients had Rai stage III or IV disease.^[1] Among the patients with central testing available, 42% had a C481 BTK mutation, 54% had 17p deletion and/or TP53 mutation, 93% had an unmutated IgHV, and 22% had an 11q deletion.^[1] Patients had received a median number of 5 prior lines of therapy (range: 2-11).^[1] The most commonly received prior BTK inhibitors were ibrutinib (97%), acalabrutinib (9%), and zanubrutinib (0.9%).^[1] The last BTK inhibitor was discontinued for refractory or progressive disease, toxicity, or other reasons in 77, 13, or 10% of patients, respectively.^[1]

Patients received pirtobrutinib 200 mg once daily until disease progression or unacceptable toxicity occurred.^[1][3] Efficacy was established based on overall response rate and duration of response as assessed by an independent review committee using 2018 International Workshop Criteria for CLL (IWCLL).^[1][3] At an estimated median follow-up duration of 15.7 months, an overall response rate of 72% (all partial responses) was observed.^[1] The median time to response was 3.7 months (range: 1.7-27.9 months), and the median duration of response was 12.2 months.^[1] Following initiation of single-agent pirtobrutinib therapy, lymphocytosis (i.e., absolute lymphocyte count >=5000/mm³ and an increase of at least 50% from baseline) occurred in 64% of patients.^[1] The median time to onset of lymphocytosis was 1.1 weeks, with 75% of cases occurring within 1.1 weeks.^[1] The median duration of lymphocytosis was 19 weeks.^[1]

Clinical Perspective

The National Cancer Institute (NCI) states that treatment of CLL must be individualized based on disease stage and behavior.^[17] Noncovalent BTK inhibitors are mentioned in the NCI guidelines as an option for the treatment of recurrent or refractory CLL.^[17]

Efficacy of pirtobrutinib has been demonstrated in heavily pretreated patients with CLL or SLL, including those with resistance or intolerance to previous covalent BTK inhibitor therapy.^{[1][3][7][8][9]} This suggests that CLL and SLL tumors maintain nearly universal dependency on B-cell receptor signaling mediated by BTK, despite previous exposure to a covalent BTK inhibitor.^[7] Sequential use of a covalent BTK inhibitor followed by pirtobrutinib may meaningfully extend the total period of clinical benefit of targeting the BTK signaling pathway.^[7] Pirtobrutinib also has demonstrated efficacy in patients with CLL relapse who received prior treatment with venetoclax.^[3][7][8] However, resistance to pirtobrutinib has been observed in patients with CLL/SLL, and more information is needed about mechanisms of resistance to the drug.^[7][9] No information is available to date on the efficacy of covalent BTK inhibitors in patients who receive pirtobrutinib first and in whom resistance develops.^[7] More data are needed to inform appropriate treatment sequencing and understand patterns of potential cross-resistance.^[7] Optimal treatment of patients who develop pirtobrutinib resistance is currently unknown.^[9] Several phase 3 trials evaluating pirtobrutinib in patients with CLL or SLL are ongoing.^[3][7][9] Because many patients with CLL or SLL require treatment with BTK inhibitors for a considerable duration, more data on the long-term safety and efficacy of pirtobrutinib are needed.^[3][7]

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential.^[1]Evaluate bilirubin and transaminases at baseline.^[1]

Patient Monitoring

Monitor for signs and symptoms of infection during therapy.^[1]Monitor patients for signs of bleeding.^[1]Monitor complete blood count (CBC) during therapy.^[1]Monitor for symptoms of arrhythmias.^[1]Monitor patients for the development of second primary malignancies.^[1]Monitor bilirubin and transaminases during therapy; monitor more frequently in patients who develop abnormal liver tests.^[1]

Premedication and Prophylaxis

In patients at increased risk for opportunistic infections, consider prophylaxis, including vaccinations and anti-infective prophylactic therapy.^[1]

Other General Considerations

Consider potential benefits and risks of withholding pirtobrutinib therapy for 3-7 days prior to and following surgery (based on the type of surgery and bleeding risk).^[1]Advise patients to use sun protection.^[1]

Administration

Administer orally once daily at approximately the same time each day without regard to food.^[1] Swallow tablets whole with water; do _not_cut, crush, or chew tablets.^[1]

If a dose of pirtobrutinib is missed by >12 hours, skip the dose and administer the next dose at the regularly scheduled time.^[1] Do not take extra tablets of the drug to make up for the missed dose.^[1]

Store pirtobrutinib tablets at 20-25^oC; excursions are permitted to 15-30^oC.^[1]

Dosage

Mantle Cell Lymphoma

For the treatment of mantle cell lymphoma in adults who have received at least 2 prior systemic therapies, including a Bruton's tyrosine kinase (BTK) inhibitor, the recommended dosage of pirtobrutinib is 200 mg once daily.^[1] Continue therapy until disease progression or unacceptable toxicity occurs.^[1]

Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults who have received at least 2 prior lines of systemic therapy, including a BTK inhibitor and a B-cell chronic lymphoma 2 (BCL-2) inhibitor, the recommended dosage of pirtobrutinib is 200 mg once daily.^[1] Continue therapy until disease progression or unacceptable toxicity occurs.^[1]

Dosage Modification for Toxicity

Withhold pirtobrutinib therapy if grade 3 or greater nonhematologic toxicity, absolute neutrophil count (ANC) <1000 to 500 cells/mm³ with fever and/or infection, ANC <500 cells/mm³ lasting >=7 days, platelet count <50,000 to 25,000 cells/mm³ with bleeding, or platelet count <25,000 cells/mm³ occurs.^[1] Upon resolution or improvement of the toxicity (i.e., return to baseline or resolution to grade 1), pirtobrutinib therapy may be resumed as described in Table 1.^[1]

Evaluate the potential risks and benefits before resuming treatment at the same dose following resolution of grade 4 nonhematologic toxicity.^[1]

Dosage adjustment is not recommended for asymptomatic lymphocytosis.^[1] Dosage adjustment may not be necessary in case of asymptomatic increases in lipase concentrations.^[1]

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Avoid concomitant use of strong CYP3A inhibitors with pirtobrutinib.^[1] If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the pirtobrutinib dosage by 50 mg daily.^[1] If the current dosage is 50 mg once daily, interrupt pirtobrutinib therapy for the duration of strong CYP3A inhibitor use.^[1] After discontinuance of the strong CYP3A inhibitor for 5 half-lives, resume pirtobrutinib at the dosage used prior to initiation of the strong CYP3A inhibitor.^[1]

Avoid concomitant use of strong or moderate CYP3A inducers with pirtobrutinib.^[1] If concomitant use with a moderate CYP3A inducer cannot be avoided and the current dosage of pirtobrutinib is 200 mg once daily, increase the pirtobrutinib dosage to 300 mg once daily.^[1] If the current pirtobrutinib dosage is 50 or 100 mg once daily, increase the pirtobrutinib dosage by 50 mg daily.^[1]

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.^[1]

Renal Impairment

No dosage adjustment is recommended in patients with mild or moderate renal impairment (estimated GFR 30-89 mL/minute).^[1]

In patients with severe renal impairment (estimated GFR 15-29 mL/minute), reduce the pirtobrutinib dosage to 100 mg once daily in patients receiving a current dosage of 200 mg once daily; otherwise, reduce the daily dosage by 50 mg.^[1] If the current dosage is 50 mg once daily, discontinue pirtobrutinib.^[1]

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.^[1]

Contraindications

None.^[1]

Warnings/Precautions

Infectious Complications

Serious and sometimes fatal infections, including bacterial, viral, or fungal infection, and opportunistic infections, have been reported in pirtobrutinib-treated patients.^[1] Grade 3 or higher infections occurred in 24% of 593 patients with hematologic malignancies receiving pirtobrutinib in the BRUIN clinical trial, with fatal infections occurring in 4.4% of patients.^[1] Pneumonia, sepsis, or febrile neutropenia occurred in 14, 6, or 4% of patients, respectively.^[1] In patients with mantle cell lymphoma (MCL) in the BRUIN study, grade 3-4 pneumonia occurred in 14% of patients.^[1] In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), grade 3 or higher infections occurred in 32% of patients, with fatal infections occurring in 8% of patients.^[1]

Opportunistic infections reported in patients receiving pirtobrutinib have included Pneumocystis jirovecii pneumonia and fungal infection.^[1]

Consider prophylaxis, including vaccinations and anti-infective prophylactic therapy, in patients who are at increased risk for infections, including opportunistic infections.^[1]

Monitor patients receiving pirtobrutinib for signs and symptoms of infection; evaluate promptly and treat appropriately if infection occurs.^[1] Based on severity, reduce the dosage of, temporarily withhold, or permanently discontinue pirtobrutinib.^[1]

Hemorrhage

Serious hemorrhagic events, including fatal events, have occurred in patients treated with pirtobrutinib in the BRUIN study.^[1] Major hemorrhage (grade 3 or higher bleeding or any CNS bleeding), including GI bleeding, was reported in 3% of the 593 patients who received the drug, with fatal hemorrhage occurring in 0.3% of patients.^[1] Overall, hemorrhagic events, excluding bruising and petechiae, of any grade of severity occurred in 17% of patients receiving pirtobrutinib in the clinical trial.^[1]

Concomitant use of pirtobrutinib with antithrombotic agents may further increase the risk of hemorrhagic events; however, in the clinical trial, major hemorrhage occurred in 2.3% of patients taking pirtobrutinib without antithrombotic agents and 0.7% of patients taking pirtobrutinib with antithrombotic agents.^[1] Consider the risks and benefits of antithrombotic agents when used concomitantly with pirtobrutinib, and monitor patients for signs of bleeding.^[1]

If bleeding occurs, based on severity, reduce the dosage of, temporarily withhold, or permanently discontinue pirtobrutinib.^[1]

Because of the risk of bleeding, consider the potential benefits and risks of withholding pirtobrutinib therapy for 3-7 days prior to and following surgery (based on the type of surgery and bleeding risk).^[1]

Myelosuppression

Cytopenias, including neutropenia, thrombocytopenia, and anemia, have been reported in patients receiving pirtobrutinib.^[1] Grade 3 or 4 neutropenia, anemia, or thrombocytopenia was reported in 26, 12, or 12%, respectively, of patients treated with pirtobrutinib in the BRUIN study.^[1] Grade 4 neutropenia or thrombocytopenia developed in 14 or 6% of patients, respectively.^[1]

Monitor CBC counts regularly during pirtobrutinib therapy.^[1] If myelosuppression occurs, based on severity, reduce the dosage of, temporarily withhold, or permanently discontinue pirtobrutinib.^[1]

Cardiac Arrhythmias

Cardiac arrhythmias, including atrial fibrillation and atrial flutter, have been reported in patients receiving pirtobrutinib.^[1] Atrial fibrillation or atrial flutter of any grade was reported in 3.2% of patients treated with pirtobrutinib in the clinical trial.^[1] Grade 3 or 4 atrial fibrillation or atrial flutter occurred in 1.5% of patients.^[1] Other serious cardiac arrhythmias (e.g., supraventricular tachycardia, cardiac arrest) occurred in 0.5% of patients.^[1]

The risk for atrial fibrillation or flutter may be increased in patients with cardiac risk factors, hypertension, or previous arrhythmias.^[1]

Monitor patients receiving pirtobrutinib for signs and symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) and manage appropriately.^[1] If arrhythmias occur, based on severity, reduce the dosage of, temporarily withhold, or permanently discontinue pirtobrutinib.^[1]

Development of Second Primary Malignancy

Second primary malignancies, including non-skin carcinomas, have occurred in 9% of 593 patients with hematologic malignancies treated with pirtobrutinib monotherapy in the BRUIN study.^[1] The most frequent malignancy was non-melanoma skin cancer, reported in 4.6% of patients.^[1] Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma.^[1]

Advise patients to use sun protection and monitor patients for the development of second primary malignancies.^[1]

Hepatotoxicity

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury, have been reported with pirtobrutinib therapy.^[1]

Bilirubin and transaminases should be evaluated at baseline and during therapy.^[1] If abnormal liver tests develop, patients should be monitored for clinical signs and symptoms of hepatotoxicity and more frequently for liver test abnormalities.^[1] Pirtobrutinib should be withheld if drug-induced livery injury is suspected and discontinued upon confirmation.^[1]

Fetal/Neonatal Morbidity and Mortality

There are no available data regarding the use of pirtobrutinib in pregnant women; however, based on animal findings, the drug may cause fetal harm.^[1] Embryofetal toxicity (e.g., structural abnormalities, altered fetal growth, embryofetal mortality) has been demonstrated in animals receiving the drug at exposures approximately 3 times the human exposure at the recommended dosage of 200 mg once daily.^[1]

If pirtobrutinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, apprise the patient of the potential hazard to the fetus.^[1] Advise females of reproductive potential to use effective contraception during treatment with pirtobrutinib and for 1 week after the last dose.^[1]

Specific Populations

Pregnancy

Pirtobrutinib may cause fetal harm if administered to pregnant women based on animal findings.^[1]

Lactation

It is not known whether pirtobrutinib is distributed into human milk or if the drug has any effect on milk production or the nursing infant.^[1] Women are advised not to breast-feed during treatment with pirtobrutinib and for 1 week after discontinuing the drug due to the potential for serious adverse reactions in the breast-fed child.^[1]

Females and Males of Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential prior to initiating pirtobrutinib therapy.^[1] Advise female patients of reproductive potential to use effective contraception during treatment with pirtobrutinib and for 1 week following the last dose of the drug.^[1]

Pediatric Use

Safety and efficacy of pirtobrutinib have not been established in pediatric patients.^[1]

Geriatric Use

Among the patients with mantle cell lymphoma (MCL) who received pirtobrutinib 200 mg daily in the clinical trial, 78% were >=65 years of age and 33% were >=75 years of age.^[1] Clinical studies of pirtobrutinib did not include sufficient numbers of patients with MCL who were <65 years of age to determine whether older patients respond differently from younger adult patients.^[1]

Among the patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who received pirtobrutinib 200 mg daily in the clinical trial, 63% were >=65 years of age and 19% were >=75 years of age.^[1] No overall differences in efficacy were observed between geriatric patients and younger adult patients.^[1]

In the pooled safety population in patients with hematologic malignancies, 68% were >=65 years of age, while 26% were >=75 years of age.^[1] Patients >=65 years of age experienced higher rates of grade 3 and higher adverse reactions and serious adverse reactions compared to patients who were <65 years of age.^[1]

Hepatic Impairment

No clinically important differences in the pharmacokinetics of pirtobrutinib were observed based on mild (total bilirubin less than or equal to the upper limit of normal [ULN] and aspartate aminotransferase [AST] above the ULN or total bilirubin >1-1.5 times the ULN and any AST), moderate (total bilirubin >1.5-3 times the ULN and any AST), or severe (total bilirubin >3 times the ULN and any AST) hepatic impairment.^[1] No dosage adjustment of pirtobrutinib is recommended in patients with mild, moderate, or severe hepatic impairment.^[1]

Renal Impairment

Following a single 200-mg oral dose, AUC of pirtobrutinib in subjects with severe renal impairment (estimated GFR 15-29 mL/minute) increased by 62% and mean unbound AUC increased by 68% compared to healthy subjects with normal renal function.^[1] Reduced dosage of pirtobrutinib is recommended in patients with severe renal impairment.^[1]

There were no clinically important differences in the pharmacokinetics of pirtobrutinib in subjects with mild (estimated GFR 60-89 mL/minute) or moderate (estimated GFR 30-59 mL/minute) renal impairment.^[1] No dosage adjustment is recommended in patients with mild or moderate renal impairment.^[1]

The effect of renal impairment requiring dialysis on the pharmacokinetics of pirtobrutinib is unknown.^[1]

Common Adverse Effects

Adverse effects reported in >=20% of patients include fatigue, musculoskeletal pain, diarrhea, COVID-19, bruising, and cough.^[1] Grade 3 or 4 laboratory abnormalities (reported in >=10% of patients): neutropenia, lymphopenia, thrombocytopenia, and anemia.^[1]

Drug Interaction Potential

Pirtobrutinib is principally metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 and direct glucuronidation by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A8 and UGT1A9, in vitro.^[1]

In vitro studies indicate that pirtobrutinib is an inhibitor of P-glycoprotein (P-gp), a moderate inhibitor of CYP2C8 and breast cancer resistance protein (BCRP), and a weak inhibitor of CYP2C19 and CYP3A.^[1]

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A

Concomitant use of a strong CYP3A inhibitor with pirtobrutinib increases pirtobrutinib systemic exposure, which may result in increased toxicity^[1] . Concomitant administration of itraconazole (a strong CYP3A inhibitor) with a single 200-mg dose of pirtobrutinib resulted in a 49% increase in pirtobrutinib AUC.^[1] Concomitant use of verapamil or diltiazem (moderate CYP3A inhibitors) is predicted to increase pirtobrutinib AUC by 30 or 20%, respectively.^[1]

Avoid concomitant use of strong CYP3A inhibitors during treatment with pirtobrutinib.^[1] If concomitant use of strong CYP3A inhibitors is necessary, reduce the dosage of pirtobrutinib by 50 mg daily.^[1] If the current dosage is 50 mg once daily, interrupt pirtobrutinib therapy for the duration of strong CYP3A inhibitor use.^[1] After discontinuance of the strong CYP3A inhibitor for 5 half-lives, resume pirtobrutinib at the dosage used prior to initiation of the strong CYP3A inhibitor.^[1]

Inducers of CYP3A

Concomitant use of pirtobrutinib with a strong or moderate CYP3A inducer decreases pirtobrutinib systemic exposure, which may reduce pirtobrutinib efficacy.^[1] Concomitant administration of a single 200-mg dose of pirtobrutinib with the strong CYP3A inducer rifampin decreased pirtobrutinib AUC by 71%.^[1] Concomitant use of efavirenz or bosentan (moderate CYP3A inducers) with pirtobrutinib is predicted to decrease pirtobrutinib AUC by 49 or 27%, respectively.^[1]

Avoid concomitant use of pirtobrutinib with strong or moderate CYP3A inducers.^[1] If concomitant use of a moderate CYP3A inducer is unavoidable, increase the pirtobrutinib dosage.^[1] If the current dosage of pirtobrutinib is 200 mg once daily, increase the dosage to 300 mg once daily; if the current dosage is 50 or 100 mg once daily, increase the daily dose by 50 mg.^[1]

Drugs Metabolized by Hepatic Microsomal Enzymes

Concomitant use of pirtobrutinib with a sensitive CYP2C8, CYP2C19, or CYP3A substrate may increase plasma concentrations of the substrate, which may increase the risk of adverse reactions for drugs that are sensitive to minimal concentration changes.^[1] Concomitant use of pirtobrutinib and oral midazolam increased the AUC and peak concentrations of midazolam (a sensitive CYP3A substrate) by 70 and 58%, respectively.^[1] Administration of pirtobrutinib did not have a substantial effect on the exposure of IV midazolam.^[1] Concomitant use of pirtobrutinib and the sensitive CYP2C8 substrate repaglinide increased the AUC and peak concentrations of repaglinide by 130 and 98%, respectively.^[1] Concomitant administration of pirtobrutinib and the sensitive CYP2C19 substrate omeprazole increased the AUC and peak concentrations of omeprazole by 56 and 49%, respectively.^[1] Pirtobrutinib did not have a substantial effect on the exposures of caffeine (sensitive CYP1A2 substrate) or S-warfarin (moderately sensitive CYP2C9 substrate).^[1]

Follow recommendations in the manufacturer's prescribing information for sensitive CYP2C8, CYP2C19, or CYP3A substrates in patients receiving these drugs concomitantly with pirtobrutinib.^[1]

Drugs Affected by Transport Systems

Concomitant use of pirtobrutinib with sensitive P-gp or BCRP substrates increases the plasma concentrations of these substrates, which may increase the risk of adverse reactions related to these substrates for drugs that are sensitive to minimal concentration changes.^[1] Administration of a single 200-mg dose of pirtobrutinib increased the AUC and peak concentrations of the sensitive P-gp substrate digoxin by 17 and 51%, respectively.^[1] Multiple doses of pirtobrutinib (200 mg daily) further increased the AUC and peak concentrations of digoxin by up to 35 and 55%, respectively.^[1] Multiple doses of pirtobrutinib (200 mg daily) increased the AUC and peak concentrations of the sensitive BCRP substrate rosuvastatin by 140 and 146%, respectively.^[1]

Follow recommendations in the manufacturer's prescribing information for sensitive P-gp or BCRP substrates in patients receiving these drugs concomitantly with pirtobrutinib.^[1]

Drugs Affecting Gastric Acidity

Concomitant administration of the proton pump inhibitor omeprazole with pirtobrutinib did not result in substantial differences in pirtobrutinib pharmacokinetics.^[1]

Anticoagulants and Antiplatelet Agents

Concomitant use of pirtobrutinib with antiplatelet or anticoagulant therapy may increase the risk of hemorrhage.^[1] If used concomitantly, monitor patients for signs of bleeding/hemorrhage.^[1]

Pirtobrutinib is a small molecule, noncovalent (reversible) inhibitor of Bruton's tyrosine kinase (BTK); the drug is an antineoplastic agent.^{[1][3][5][6][7][8][9]} BTK is an essential signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways.^[1][5][8] Within B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.^[1] Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity.^{[1][5][7][8][9]} The reversible binding mode of pirtobrutinib does not require covalent modification of the C481 residue; therefore, pirtobrutinib retains potency in the context of C481 mutations that cause resistance to covalent BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib).^[7][8][9] In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation.^[1] Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models.^[1] At the recommended pirtobrutinib dosage of 200 mg once daily, BTK occupancy is maintained throughout the dosing interval, regardless of the intrinsic rate of BTK turnover.^{[1][3][5][7][9]} Unlike other BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib), pirtobrutinib binds to BTK in a noncovalent manner.^[17]

Pirtobrutinib AUC and peak concentrations increase proportionally following single oral doses ranging from 300-800 mg (1.5-4 times the approved recommended dosage) and multiple once-daily doses ranging from 25-300 mg (0.125-1.5 times the recommended dosage).^[1][3] Following repeated doses of 200 mg once daily, steady-state concentrations are achieved within 5 days and the accumulation ratio for the drug is 1.63.^[1] The absolute bioavailability of pirtobrutinib after a single oral 200-mg dose is 85.5% (range: 75.9-90.9%).^[1] The median time to reach peak plasma concentrations is approximately 2 hours (range: 0.83-4.15 hours).^[1] Administration of pirtobrutinib with a high-fat, high-calorie meal (approximately 800-1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500-600 calories from fat) in healthy subjects resulted in a 23% decrease in pirtobrutinib peak concentrations and a 1-hour delay in time to peak plasma concentrations; no effect on pirtobrutinib AUC was observed, and the effects of food on pirtobrutinib pharmacokinetics are not considered clinically important.^[1] In vitro, pirtobrutinib is 96% bound to plasma proteins, and protein binding of the drug is independent of concentration.^[1] The mean blood-to-plasma ratio is 0.79.^[1] Pirtobrutinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 and direct glucuronidation by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A8 and UGT1A9, in vitro.^[1] Following a single radiolabeled 200-mg dose of pirtobrutinib in healthy subjects, 37% of the dose was recovered in feces (18% unchanged) and 57% in urine (10% unchanged).^[1] The effective elimination half-life of pirtobrutinib is approximately 19 hours.^[1] The pharmacokinetics of pirtobrutinib do not appear to be affected by age (range: 22-95 years), sex, race/ethnicity (based on a study population that was 84% white and 7% Asian), or body weight (range: 35.7-152 kg).^[1]

Advise patients to read the manufacturer's patient information.^[1]Instruct patients to take pirtobrutinib once daily at approximately the same time each day without regard to food.^[1] If a dose is missed, administer the missed dose on the same day as soon as it is remembered.^[1] If the dose is missed by >12 hours, skip the missed dose and take the next dose at the regularly scheduled time the following day.^[1] Advise patients to swallow the tablets whole with water and not to cut, crush, or chew tablets.^[1]Risk of serious, potentially fatal, infection.^[1] Report signs or symptoms of possible infection (e.g., fever, chills, weakness) to clinician.^[1]Risk of hemorrhage.^[1] Inform clinician of signs or symptoms of bleeding.^[1] Notify clinician of any planned surgeries; pirtobrutinib therapy may need to be interrupted for major surgeries.^[1]Risk of myelosuppression.^[1] Periodic monitoring of CBC counts is necessary during pirtobrutinib therapy.^[1]Risk of cardiac arrhythmias.^[1] Inform clinician if palpitations, dizziness, fainting, chest discomfort, or shortness of breath occurs.^[1]Possible risk of developing a second primary malignancy (e.g., skin cancer, other solid tumors).^[1] Use sun protection and monitor for development of other cancers.^[1]Risk of hepatotoxicity.^[1] Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may occur.^[1] Advise patients to contact their clinician immediately if they experience abdominal discomfort, dark urine, or jaundice.^[1]Risk of fetal harm.^[1] Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed.^[1] Apprise patient of potential hazard to the fetus if used during pregnancy.^[1] Females of reproductive potential should use effective contraception during therapy and for 1 week after the last dose.^[1] Due to potential adverse effects on the breast-fed child, do not breast-feed during treatment and for 1 week after the last dose.^[1]Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^[1]Inform patients of other important precautionary information.^[1]

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pirtobrutinib is available through designated specialty pharmacies.^[4] Consult manufacturer's website for specific availability information.^[4]

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