ALIPITOBTINIB Pirtobrutinib 100mg

I. Basic Drug Information

Generic Name: Pirtobrutinib Tablets

Other Names: Pirtobrutinib, Jaypirca, ALIPITOBTINIB

English Name: Pirtobrutinib

Specification: 100 mg/tablet; 30 tablets/bottle

Manufacturer: Lao United Pharmaceutical Group Co., Ltd.

Approval Number (Lao National Drug Administration): 09 L 1384/25

Drug Class: Bruton's Tyrosine Kinase Inhibitor (BTK Inhibitor)

II. Mechanism of Action

Pirtobrutinib is a highly selective, reversible BTK inhibitor.

1.  Target: Bruton's Tyrosine Kinase (BTK). BTK is a key protein in the B-cell receptor signaling pathway and plays a crucial role in the proliferation, differentiation, and survival of B cells. In certain B-cell malignancies, this pathway is abnormally and constitutively activated.

2.  Key Characteristics:

Reversible Binding: Unlike first- and second-generation irreversible BTK inhibitors (e.g., Ibrutinib, Zanubrutinib, Acalabrutinib), Pirtobrutinib binds to BTK in a reversible manner. This characteristic may result in distinct resistance and safety profiles. 

Overcoming Resistance: This represents its most significant clinical value. For patients who have developed resistance (particularly due to BTK C481 mutations) or experienced disease progression following prior treatment with irreversible BTK inhibitors, Pirtobrutinib remains capable of effectively inhibiting BTK activity, thereby continuing to control tumor growth. 

High Selectivity: It demonstrates high selectivity for BTK, which may help reduce adverse reactions caused by off-target effects.

III. Indications

Pirtobrutinib has been approved in certain countries and regions for the treatment of the following hematological malignancies (please refer to approvals issued by local drug regulatory authorities for specific details):

1.  Mantle Cell Lymphoma (MCL):

Indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma who have received at least two prior lines of systemic therapy, including a BTK inhibitor. 2. Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma:

Indicated for the treatment of adult patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) who have received at least two prior lines of systemic therapy, including a BTK inhibitor and a BCL-2 inhibitor (such as venetoclax).

Key Point: Pirtobrutinib is positioned as a subsequent-line therapy, primarily intended for patients who have developed resistance to, or are intolerant of, previous treatments—particularly irreversible BTK inhibitors.

IV. Dosage and Administration

Route of Administration: Oral.

Recommended Dosage: 200 mg once daily.

Administration Instructions:

Swallow the tablet whole; do not chew, crush, or split it.

May be taken with or without food.

If a dose is missed, take the missed dose as soon as possible unless more than 12 hours have elapsed since the scheduled time. If more than 12 hours have passed, skip the missed dose and take the next dose at the regularly scheduled time the following day. Do not take a double dose to make up for a missed dose.

Treatment Duration: Continue treatment until disease progression or until unacceptable toxicity occurs.

V. Dosage Adjustments and Management

In the event of adverse reactions, the physician may recommend temporary interruption of treatment, dose reduction, or permanent discontinuation of the drug, depending on the severity of the reaction.

Starting Dose: 200 mg once daily.

Dose Reduction Levels:

First Dose Reduction: 100 mg once daily. 

Second Dose Reduction: 50 mg once daily.

If the patient is unable to tolerate the 50 mg once-daily dose, treatment should be permanently discontinued.

Specific dosage adjustments (e.g., for infections, hematologic toxicities, non-hematologic toxicities, etc.) must be strictly followed according to physician's orders.

VI. Contraindications

Contraindicated in patients with a history of severe hypersensitivity reactions to Pirtobrutinib or to any of its excipients.

VII. Warnings and Precautions

1. Infections:

Opportunistic infections, bacterial infections, viral infections, and fungal infections—some of which have been severe or fatal—have been reported in patients treated with Pirtobrutinib. During and after treatment, patients should be closely monitored for signs and symptoms of infection—such as fever and neutropenia—and appropriate symptomatic treatment should be administered promptly.

Prophylactic anti-infective therapy should be considered in accordance with standard guidelines.

2.  Hemorrhage:

BTK inhibitors may cause serious hemorrhagic events.

Intracranial hemorrhage, gastrointestinal hemorrhage, and hemorrhage at other sites have been reported.

Assess patients for bleeding risk, particularly those concomitantly receiving antiplatelet agents or anticoagulants. Prior to undergoing surgery, consider temporarily withholding the medication based on the clinical situation.

3.  Cytopenias:

Neutropenia, thrombocytopenia, and anemia may occur.

Complete blood counts should be monitored prior to and periodically during treatment.

Depending on the severity, temporary discontinuation of the medication, dose reduction, or supportive care (e.g., growth factors, blood transfusions) may be required.

4.  Arrhythmias:

Atrial fibrillation and atrial flutter have been reported.

Patients should be periodically monitored for signs and symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) during treatment. If arrhythmias occur, appropriate management should be initiated, and dose adjustment should be considered based on severity.

5.  Secondary Primary Malignancies:

Similar to other BTK inhibitors, secondary primary malignancies—including skin cancers and other solid tumors—have been reported in patients treated with Pirtobrutinib. Patients should undergo periodic skin examinations.

6.  Embryo-Fetal Toxicity:

Based on animal studies, Pirtobrutinib may cause fetal harm.

Females of reproductive potential must use effective contraception during treatment and for at least 1 week following the last dose. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 1 week following the last dose.

VIII. Adverse Reactions

In clinical studies, common adverse reactions included:

Very Common (≥20%) Adverse Reactions:

General Disorders: Fatigue. 

Musculoskeletal: Musculoskeletal pain, arthralgia. 

Hematologic Toxicity: Neutropenia, anemia, thrombocytopenia. Gastrointestinal: Diarrhea. 

Laboratory Abnormalities: Lymphocytosis (associated with drug-induced mobilization of lymphocytes from lymphoid tissues).

Common (<20%) but Important Adverse Reactions:

Infections (e.g., pneumonia), contusion, nausea, dyspnea, rash, pyrexia, constipation, edema, dizziness, etc.

Important and Serious Adverse Reactions (See [Warnings and Precautions] for details):

Serious infections

Serious hemorrhage

Serious cytopenias

Atrial fibrillation/flutter

IX. Drug Interactions

Pirtobrutinib is a substrate of CYP3A and an inhibitor of the transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).

1.  Strong or Moderate CYP3A Inhibitors:

Examples: Itraconazole, voriconazole, clarithromycin, ritonavir, grapefruit juice. 

Effect: Increases Pirtobrutinib plasma concentrations, thereby increasing the risk of adverse reactions. 

Recommendation: Concomitant use should be avoided. If concomitant use cannot be avoided, the dosage of Pirtobrutinib should be reduced.

2.  Strong or Moderate CYP3A Inducers:

Examples: Rifampin, carbamazepine, St. John’s wort, phenytoin. 

Effect: Decreases Pirtobrutinib plasma concentrations, potentially leading to reduced efficacy. 

Recommendation: Concomitant use should be avoided.

3.  Effects of Pirtobrutinib as an Inhibitor:

Pirtobrutinib may increase the plasma concentrations of drugs that are substrates of P-gp or BCRP. 

Examples of Affected Drugs: Digoxin (P-gp substrate), rosuvastatin (BCRP substrate). 

Recommendation: When co-administered, monitor closely for adverse reactions associated with these substrate drugs and consider reducing their dosages.

X. Use in Specific Populations

Pregnant Women: Based on its mechanism of action, Pirtobrutinib may cause fetal harm; therefore, it is contraindicated. Lactating Women: It is not known whether Pirtobrutinib is excreted in human milk. Given the potential for serious adverse reactions in nursing infants, breastfeeding should be discontinued during treatment and for at least one week following the final dose.

Pediatric Patients: Safety and efficacy have not been established.

Geriatric Patients: In clinical studies, no overall differences in safety or efficacy were observed between patients aged 65 and older and younger patients.

Hepatic/Renal Impairment:

Mild to Moderate Hepatic Impairment: No dose adjustment is required. 

Severe Hepatic Impairment: A recommended dosage has not been established; use with caution. 

Mild to Moderate Renal Impairment: No dose adjustment is required. 

Severe Renal Impairment: A recommended dosage has not been established; use with caution.

XI. Overdosage

There is currently no specific antidote.

Overdosage may exacerbate adverse reactions, particularly bleeding and cytopenias.

In the event of an overdose, the medication should be discontinued, and immediate supportive care and symptomatic treatment should be initiated, including close monitoring of complete blood counts and signs of bleeding.

XII. Storage

Store at 20°C to 25°C; excursions between 15°C and 30°C are permitted.

Store in the original packaging to protect from moisture.

Keep out of the reach of children.

Final Reminder: This content serves as an informational summary and is not a substitute for professional medical advice. Your treating physician is the most reliable and up-to-date source for information regarding your treatment. Please ensure you communicate closely with your healthcare team and report any discomfort or adverse effects you experience.