Jaypirca (Pirtobrutinib): Uses, Dose, MOA, Side effects

Jaypirca (Pirtobrutinib) is a medication that is used to treat mantle cell lymphoma (MLC) that is relapsed or irresponsive to other treatments. It is also safe and effective to be used in children.

Brand Name: Jaypirca

Medical Name: Pirtobrutinib

Class: BTK (Bruton’s Tyrosine Kinase) Inhibitor

FDA-Approval Date: 27th January 2023

Primary Indication: Refractory or relapsed Mantle Cell Lymphoma

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Jaypirca (Pirtobrutinib) FDA-Approved Indications:

JAYPIRCA is a Bruton’s Tyrosine Kinase Inhibitor (BTK-Inhibitor). It has been approved by the FDA for treating mantle cell lymphoma in patients who have not responded adequately to previous therapies including a BTK inhibitor and at least two first-line of chemotherapeutic drugs.

It is indicated for the treatment of relapsed cases or refractory cases of mantle cell lymphoma.

Jaypirca (Pirtobrutinib) Dose Recommendation:

The usual recommended dose is 200 mg orally once a day. The treatment is continued until the toxic effects of the drugs are observed or the disease is noted to progress despite the treatment.

The tablets should be swallowed whole with water. Avoid cutting, crushing, or chewing them. The drug should be taken daily at the same time of the day without regard to meals or food.

If a person forgets to take the dose at the scheduled time, it should be taken immediately. However, if more than 12 hours have passed, skip the dose and wait for the next dose.

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Dose modification due to side effects occurrence:

Adverse Reaction	Dosage Modification
First Occurrence	Interrupt JAYPIRCA until the adverse reaction is resolved or reduced to Grade 1 or baseline. Restart the dose at the usual recommended dose of 200 mg once daily.
Second Occurrence	Withhold the treatment until the side effects have resolved or improved to at least Grade 1. Restart the dose at half the usual recommended dose (100 mg once daily).
Third Occurrence	Stop the treatment until the side effects have resolved or improved to Grade 1. Restart the dose at a much lower dose i.e. 50 mg once daily.
Fourth Occurrence	Discontinue the treatment permanently.

Lymphocytosis can occur however, in asymptomatic patients, adjusting the dose is not recommended.

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Dosage modifications for JAYPIRCA in specific situations:

Situation	Dosage Modification
Severe Renal Impairment (eGFR 15-29 mL/min)	Reduce the dose to 100 mg orally once daily if the current dose is 200 mg once daily, otherwise, reduce to 50 mg. Discontinue the treatment if the current dose is 50 mg once daily.
Mild to Moderate Renal Impairment (eGFR 30-89 mL/min)	No modification recommended
Concomitant use with Strong CYP3A Inhibitors	Avoid it if possible. If unavoidable, reduce the JAYPIRCA dose by 50 mg. Interrupt JAYPIRCA treatment if currently taking 50 mg once daily. Resume the previous dose after 5 half-lives of the CYP3A inhibitor.
Concomitant use with Strong or Moderate CYP3A Inducers	Avoid concomitant use with strong or moderate CYP3A inducers. However, if one can not avoid it, increase the dose to 300 mg. For current dosages of 50 mg or 100 mg once daily, increase by 50 mg.

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Jaypirca Dose form and strength:

Tablet	Appearance	Debossing
50 mg	Blue, arc-triangle shaped	“Lilly 50” on one side, “6902” on other
100 mg	Blue, round	“Lilly 100” on one side, “7026” on other

Contraindications to Pirtobrutinib (Jaypirca):

No contraindication is given in the FDA prescribing information.

The warnings and precautions for JAYPIRCA are listed in the table below:

Safety Information	Recommendations
Infections	Consider prophylaxis in patients at increased risk. Monitor for the clinical features of infection and treat promptly with appropriate antibiotics. In severe infection, the treatment may be discontinued.
Hemorrhage	Consider the risk of bleeding and monitor (for bleeding) in patients on antithrombotic drugs. The treatment may be discontinued in severe cases and after major surgery.
Cytopenias	Monitor for cytopenias and adjust or discontinue the treatment if required.
Atrial Fibrillation/Flutter	Monitor for arrhythmias. Educate the patients to report palpitations and shortness of breath. In severe cases, the treatment may be discontinued.
Second Primary Malignancies	Advise patients to use sunscreens. Monitor for second primary malignancies.
Embryo-Fetal Toxicity	The drug is toxic to the fetus. Ensure effective contraception during the treatment and one week after the treatment.

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Side effects of Jaypirca (Pirtobrutinib):

Side Effects	Description
Severe
Infections	Fatal and serious infections and sepsis can occur in patients with febrile neutropenia
Hemorrhage	Fatal and serious bleeding including major bleeding episodes can occur.
Cytopenias	Grade 3 or 4 cytopenias
Atrial Fibrillation and Atrial Flutter	Atrial fibrillation and atrial flutter
Secondary Malignancies	Solid tumors and melanoma
Common
Infections	Grade 3 or higher infections especially pneumonia
Hemorrhage	Bleeding of any grade, excluding bruising and petechiae
Cytopenias	Neutropenia, anemia, thrombocytopenia
Atrial Fibrillation and Atrial Flutter	Atrial fibrillation or flutter
Less Common
Infections	Opportunistic infections
Hemorrhage	Major bleeding especially with the concomitant use of antithrombotic drugs
Cytopenias	Grade 4 neutropenia and thrombocytopenia
Embryo-Fetal Toxicity	Fetal harm

Side effects experience in clinical trials:

Adverse Reactions (by System Organ Class)	Rate (%)
Neutropenia	41
Anemia	37
Thrombocytopenia	27
Tiredness	27
Skeletal pain	26
Lymphocytopenia	24
Bruising	20
Diarrhea	20

Drug interactions:

Drugs	Effect on JAYPIRCA	Recommendation
Strong CYP3A Inhibitors	Increases Jaypirca’s systemic exposure	Avoid concomitant use of strong CYP3A inhibitors. May reduce the dose of JAYPIRCA if the strong CYP3A4 inhibitor can not be avoided.
Strong or Moderate CYP3A Inducers	Decreases Jaypirca’s systemic exposure	Avoid concomitant use of strong or moderate CYP3A inducers. If moderate CYP3A inducers are unavoidable, increase the JAYPIRCA dosage
Effect of JAYPIRCA on Other Drugs	P-gp inhibitor, moderate CYP2C8 and BCRP inhibitor, and weak CYP2C19 and CYP3A inhibitor	Increases plasma concentrations of sensitive P-gp, CYP2C8, BCRP, CYP2C19, or CYP3A substrates
Risks Associated with Increased Concentrations of Substrates	This may increase the risk of adverse reactions	Follow recommendations for sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP substrates provided in their approved product labeling

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Use of Jayprica in specific populations:

Category	Description
Pediatric Use	Not studied in children.
Geriatric Use	Data is limited however, older people are at an increased risk of developing side effects.
Renal Impairment	No need to adjust the dose for mild and moderate renal impairment. In severe renal impairment, reduce the dose.
Hepatic Impairment	Dosage adjustment is not recommended in patients with liver disease of any severity.
Pregnancy
Risk Summary	Jaypirca is toxic to the fetus. Pregnancy should be avoided using effective contraception during the treatment and for at least one week after the last dose.
Lactation
Risk Summary	No information is available. Breastfeeding is not recommended during the treatment and at least for a week after the last dose.
Females and Males of Reproductive Potential
Pregnancy Testing	Test for pregnancy in females of reproductive ages before initiating the treatment.
Contraception	Effective contraception is recommended during the treatment for at least one week after the last dose.

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Mechanism of Action (MOA) of Pirtobrutinib (Jaypirca):

Pirtobrutinib belongs to the class of medicines called Bruton’s tyrosine kinase (BTK) inhibitors.

BTK is an important signaling protein for the B-cell antigen receptor (BCR) and cytokine receptor pathways.

BTK is a signaling protein that activates pathways that are essential for B-cell functions such as proliferation, trafficking, chemotaxis, and adhesion.

Pirtobrutinib targets both the normal BTK and BTK with C481 mutations resulting in the inhibition of BTK kinase activation of B cells. Hence, it inhibits BTK-mediated functions of B-cells CD69 expression and proliferation.

Cardiac Electrophysiology:

No significant effect on the QTc interval.

Pharmacokinetics	Information
Dose Proportionality	Pirtobrutinib exposure (AUC) and Cmax increase proportionally
Steady State	5 days
Absolute bioavailability	85.5% (range 75.9% to 90.9%).
Peak plasma concentration	2 hours
Effect of Food	A high-fat meal decreased the Cmax of Pirtobrutinib by 23% and delayed the Tmax by 1 hour.
Protein binding	96%.
Elimination	19 hours
Metabolism	CYP3A4 Direct glucuronidation by UGT1A8 and UGT1A9.
Excretion	Feces: 37% (18% unchanged) and Urine: 57% (10% unchanged).

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Clinical studies:

Aspect	Details
Study Name	BRUIN (NCT03740529) [Ref]
Participants	The study enrolled 120 patients with mantle cell lymphoma who had been previously treated with Bruton’s tyrosine kinase (BTK) inhibitors. Those with active CNS lymphoma, who had undergone allogeneic HSCT, or had received CAR) T-cell therapy within 60 days were excluded from the study.
Treatment	Enrolled patients were given JAYPIRCA orally at a dose of 200 mg once daily.
Outcome	Overall response rate (ORR) and duration of response (DOR) were evaluated based on 2014 Lugano criteria by an independent review committee (IRC)
Results	The median age of patients was 71 years (79% were male) ORR was 66.7% (80/120) with a complete response (CR) rate of 28.3% (34/120) and partial response (PR) rate of 38.3% (46/120); the median duration of response was 19.5 months.

Conclusion: In patients with MCL who had previously been treated with a BTK inhibitor, JAYPIRCA demonstrated an ORR of 66.7% with a median duration of response of 19.5 months.

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Patient counseling information:

Topic	Counseling Information
Patient Labeling	Patients should read the FDA handout.
Infections	Serious infections can occur during the treatment. Patients should report any signs of infection instantly
Bleeding	Bleeding can occur. During major surgeries, the treatment may be temporarily stopped.
Cytopenias	Frequent monitoring of blood counts is important to identify marrow toxicity earlier.
Atrial arrhythmia	Atrial fibrillation and flutter have been reported during the treatment. patients should be asked to report symptoms of shortness of breath and palpitations.
Second Primary Malignancies	There is a risk of skin cancer and other solid tumors. Patients should limit sun exposure and use sunscreens. Monitoring for solid tumors is also important.
Embryo-Fetal Toxicity	The drug is toxic to the fetus. Effective contraception should be used during the treatment and at least one week after the last dose.
Lactation	Breastfeeding is not recommended until one week after the last dose.
Administration	The drug should be taken daily at the scheduled time. Crushing the tablet, chewing, or cutting is not recommended. In addition, one should not make up for a missed dose if more than 12 hours have passed.