Pirtobrutinib (Monograph)

Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; noncovalent (reversible) inhibitor of Bruton's tyrosine kinase (BTK).

Uses for Pirtobrutinib

Mantle Cell Lymphoma (MCL)

Treatment of relapsed or refractory MCL in adults who have received at least 2 lines of prior systemic therapy, including a BTK inhibitor; designated an orphan drug by FDA for treatment of MCL.

This indication is approved under accelerated approval based on overall response rate; clinical benefit (e.g., increased survival) not established. Continued approval may be contingent on verification and description of clinical benefit in additional trials.

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Treatment of CLL or SLL in adults who have received at least 2 prior lines of therapy, including a BTK inhibitor and a B-cell chronic lymphoma 2 (BCL-2) inhibitor (e.g., venetoclax); designated an orphan drug by FDA for treatment of CLL and SLL.

This indication is approved under accelerated approval based on overall response rate; clinical benefit (e.g., increased survival) not established. Continued approval may be contingent on verification and description of clinical benefit in additional trials.

Related/similar drugs

Revlimid, Imbruvica, Venclexta, rituximab, cyclophosphamide, Rituxan, lenalidomide

Pirtobrutinib Dosage and Administration

General

Pretreatment Screening

• Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Patient Monitoring

• Monitor for signs and symptoms of infection during therapy.

• Monitor patients for signs of bleeding.

• Monitor CBC counts during therapy.

• Monitor for symptoms of arrhythmias.

• Monitor patients for the development of second primary malignancies.

Premedication and Prophylaxis

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

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).

• Advise patients to use sun protection.

Administration

Oral Administration

Administer orally once daily at approximately the same time each day without regard to food.

Swallow tablets whole with water; do not cut, crush, or chew tablets.

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

Dosage

Adults

Mantle Cell Lymphoma

Oral

200 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Oral

200 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Interrupt therapy if grade 3 or greater nonhematologic toxicity, 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. Following recovery from toxicity (i.e., return to baseline or resolution to grade 1), resume therapy as described in Table 1.

Evaluate potential risks and benefits before resuming treatment at same dose following resolution of grade 4 nonhematologic toxicity.

Dosage adjustment not recommended for asymptomatic lymphocytosis.

Dosage adjustment may not be necessary in case of asymptomatic increases in lipase.

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

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

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

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations for patients with hepatic impairment.

Renal Impairment

No dosage adjustment recommended in patients with mild or moderate renal impairment (estimated GFR 30–89 mL/minute).

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

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.

Cautions for Pirtobrutinib

Contraindications

None.

Warnings/Precautions

Infectious Complications

Serious and sometimes fatal infections, including bacterial, fungal, or viral infections, and opportunistic infections, observed.

Pneumonia was the most commonly reported grade 3 or 4 infection. Opportunistic Infections, including Pneumocystis jirovecii pneumonia and fungal infections, also observed.

Consider prophylaxis, including vaccinations and anti-infective prophylactic therapy, in patients at increased for opportunistic infections.

Monitor for signs and symptoms of infection during therapy and treat promptly if infection occurs.

If infection occurs, based on severity, reduce the dosage of, temporarily withhold, or permanently discontinue pirtobrutinib.

Hemorrhage

Serious hemorrhagic events, including fatal cases, observed. Major hemorrhage (serious or grade 3 or higher bleeding or any CNS system bleeding) reported in 3% of patients treated with pirtobrutinib in a clinical trial.

Possible increased risk of hemorrhagic events with concomitant use of pirtobrutinib and antithrombotic agents. Consider risks and benefits and monitor patients for signs of bleeding during concurrent use.

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

Consider potential benefits and risks of withholding pirtobrutinib therapy for 3–7 days prior to and following surgery.

Myelosuppression

Cytopenias, including neutropenia, thrombocytopenia, and anemia, reported. Serious (grade 3 or 4) cytopenias observed.

Monitor CBC counts regularly. If myelosuppression occurs, interrupt therapy, reduce dosage, or discontinue therapy as appropriate.

Cardiac Arrhythmias

Cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, supraventricular tachycardia, cardiac arrest) observed.

Risk may be increased in patients with cardiac risk factors, including hypertension or previous arrhythmias.

Monitor for symptoms of arrhythmias and manage appropriately. If arrhythmias occur, interrupt therapy, reduce dosage, or discontinue therapy as appropriate.

Development of Second Primary Malignancy

Second primary malignancies, including skin cancers and other solid tumors, reported in 9% of pirtobrutinib-treated patients in the clinical trial. Non-melanoma skin cancer was the most frequently reported second primary malignancy, occurring in 4.6% of pirtobrutinib-treated patients.

Monitor patients for the development of second primary malignancies and advise patients to avoid sun exposure.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity (e.g., structural abnormalities, altered fetal growth, embryofetal mortality) observed in animals.

If used during pregnancy, apprise of potential fetal hazard. Advise females of reproductive potential to use effective contraception during treatment and for 1 week after last dose.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether pirtobrutinib is distributed into human milk or if drug has any effect on milk production or breast-fed infant.

Breast-feeding is not recommended during treatment with pirtobrutinib and for 1 week after discontinuance of the drug due to the potential for severe adverse events in the breast-fed child.

Females and Males of Reproductive Potential

Pregnancy testing recommended for females of reproductive potential prior to initiating pirtobrutinib therapy.

Advise female patients of reproductive potential to use effective contraception during treatment with pirtrobrutinib and for 1 week following the last dose of the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Among the patients with MCL who received pirtobrutinib 200 mg daily in the clinical trial, 78% were ≥65 years of age and 33% were ≥75 years of age. 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.

Among the patients with CLL/SLL who received pirtobrutinib 200 mg daily in the clinical trial, 63% were ≥65 years of age and 19% were ≥75 years of age. No overall differences in efficacy were observed between geriatric patients and younger adult patients.

In the pooled safety population in patients with hematologic malignancies, 68% were ≥65 years of age and 26% were ≥75 years of age. 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.

Hepatic Impairment

Mild, moderate, or severe hepatic impairment does not substantially alter pharmacokinetics.

Renal Impairment

Increased systemic exposure in patients with severe renal impairment. Dosage adjustment required in patients with severe renal impairment.

Mild or moderate renal impairment does not substantially affect pirtobrutinib pharmacokinetics.

Not studied in patients with renal impairment who are undergoing dialysis.

Common Adverse Effects

Adverse effects (reported in ≥20% of patients): Fatigue, musculoskeletal pain, diarrhea, COVID-19, bruising, cough.

Grade 3 or 4 laboratory abnormalities (reported in ≥10% of patients): Neutropenia, lymphopenia, thrombocytopenia, anemia.

Drug Interactions

Principally metabolized by CYP3A4 and direct glucuronidation by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A8 and UGT1A9, in vitro.

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.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A inhibitors: Possible increased systemic exposure to, and increased toxicity of, pirtobrutinib. Avoid concomitant use; if concomitant use is necessary, reduce dosage of pirtobrutinib by 50 mg daily. If current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib therapy for duration of strong CYP3A inhibitor use. After discontinuance of the strong CYP3A inhibitor for 5 half-lives, resume pirtobrutinib at dosage used prior to initiation of strong CYP3A inhibitor.

Moderate CYP3A inhibitors: Possible increased systemic exposure to, and increased toxicity of, pirtobrutinib.

Strong or moderate inducers of CYP3A: Possible decreased systemic exposure to, and decreased therapeutic efficacy of, pirtobrutinib. Avoid concomitant use. If concomitant use of moderate CYP3A inducer is necessary, increase pirtobrutinib dosage. If current pirtobrutinib dosage is 200 mg once daily, increase to 300 mg once daily; if current dosage is 50 or 100 mg once daily, increase daily dose by 50 mg.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2C8, CYP2C19, or CYP3A: Possible increased systemic exposure and toxicity of the substrate drug. Follow recommendations in manufacturer’s prescribing information for sensitive CYP2C8, CYP2C19, or CYP3A substrates if used concomitantly with pirtobrutinib.

Drugs Affected by Transport Systems

P-gp or BCRP substrates: Possible increased exposure and toxicity of these substrates. Follow recommendations in manufacturer’s prescribing information for sensitive P-gp or BCRP substrates if used concomitantly with pirtobrutinib.

Specific Drugs

Pirtobrutinib Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability following a single oral 200-mg dose: 85.5% (range: 75.9–90.9%).

Median time to reach peak plasma concentrations: Approximately 2 hours (range: 0.83–4.15 hours).

AUC and peak concentrations increase proportionally following single oral doses ranging from 300–800 mg (1.5–4 times the approved recommended dosage) and once daily doses ranging from 25–300 mg (0.125–1.5 times the recommended dosage).

Steady state is achieved within 5 days of once daily dosing.

Accumulation ratio of 1.63 based on AUC observed following multiple doses of 200 mg once daily.

Food

High-fat, high-calorie meal did not substantially affect pirtobrutinib pharmacokinetics. Peak concentrations decreased by 23% and time to peak plasma concentrations delayed by 1 hour compared with administration under fasting conditions; no effect on AUC observed.

Special Populations

Severe renal impairment (estimated GFR 15–29 mL/minute): AUC increased by 62% and mean unbound AUC increased by 68% compared to healthy subjects with normal renal function.

Mild (estimated GFR 60–89 mL/minute) or moderate (estimated GFR 30–59 mL/minute) renal impairment: Pharmacokinetics not substantially affected.

Renal impairment requiring dialysis: Data not available.

Mild, moderate, or severe hepatic impairment: Pharmacokinetics not substantially affected.

No substantial differences in pharmacokinetics of pirtobrutinib observed based on age (range: 22–95 years), sex, race/ethnicity (based on patient population that was 84% white, 7% Asian) , or body weight (range: 35.7–152 kg).

Distribution

Extent

Not known whether pirtobrutinib is distributed into human milk.

Plasma Protein Binding

96%; independent of concentration in vitro.

Elimination

Metabolism

Primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9, in vitro.

Elimination Route

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).

Half-life

Approximately 19 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

• Selectively and reversibly inhibits BTK, an essential signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.

  Pirtobrutinib binds to wild type BTK and BTK harboring C481mutations, leading to inhibition of BTK kinase activity.

• Within B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

• Pirtobrutinib binds to wild type BTK and BTK harboring C481mutations, leading to inhibition of BTK kinase activity.

• In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models.

• Unlike other BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib), pirtobrutinib binds to BTK in a noncovalent manner.

Advice to Patients

• Advise patients to read the manufacturer’s patient information.

• Instruct patients to take pirtobrutinib once daily at approximately the same time each day without regard to food. If a dose is missed, administer the missed dose on the same day as soon as it is remembered. 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. Advise patients to swallow the tablets whole with water and not to cut, crush, or chew tablets.

• Risk of serious, potentially fatal, infection. Report signs or symptoms of possible infection (e.g., fever, chills, weakness) to clinician.

• Risk of hemorrhage. Inform clinician of signs or symptoms of bleeding. Notify clinician of any planned surgeries; pirtobrutinib therapy may need to be interrupted for major surgeries.

• Risk of myelosuppression. Periodic monitoring of CBC counts is necessary during pirtobrutinib therapy.

• Risk of cardiac arrhythmias. Inform clinician if palpitations, dizziness, fainting, chest discomfort, or shortness of breath occurs.

• Possible risk of developing a second primary malignancy (e.g., skin cancer, other solid tumors). Use sun protection and monitor for development of other cancers.

• Risk of fetal harm. Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Apprise patient of potential hazard to the fetus if used during pregnancy. Females of reproductive potential should use effective contraception during therapy and for 1 week after the last dose. Due to potential adverse effects on the breast-fed child, do not breast-feed during treatment and for 1 week after the last dose.

• 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.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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.

Distribution of pirtobrutinib is restricted. Consult manufacturer's website for specific availability information.

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