Dosing & Uses
Dosage Forms & Strengths
tablet
- 50mg
- 100mg
Mantle Cell Lymphoma
Indicated for relapsed or refractory mantle cell lymphoma (MCL) after at least 2 lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor
200 mg PO qDay
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Asymptomatic lymphocytosis: Dose modification not recommended
Asymptomatic lipase increase: May not necessarily warrant a dose modification
Hematologic toxicities
- NOTE: Based on starting dose of 200 mg qDay
- Absolute neutrophil count (ANC) 0.5 to <1 x 109/L with fever and/or infection
- ANC <0.5 x 109/L lasting ≥7 days
- Platelet count 25 to <50 x 109/L with bleeding
- Platelet count <25 x 109/L
-
Modification
- First occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at original dose (200 mg qDay)
- Second occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at 100 mg qDay
- Third occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at 50 mg qDay
- Fourth occurrence: Discontinue treatment
Nonhematologic toxicities
- Grade ≥3 nonhematologic toxicity
- Evaluate benefit-risk before resuming at same dose for a Grade 4 nonhematologic toxicity
- First occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at original dose (200 mg qDay)
- Second occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at 100 mg qDay
- Third occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at 50 mg qDay
- Fourth occurrence: Discontinue treatment
Coadministration with strong CYP3A inhibitors
- Avoid coadministration
- If unavoidable, reduce pirtobrutinib to 50 mg
- If current pirtobrutinib dose is 50 mg qDay, discontinue treatment for the duration of strong CYP3A inhibitor use
- After strong CYP3A inhibitor has been discontinued for 5 half-lives, resume pirtobrutinib at the dose taken before the strong CYP3A inhibitor was initiated
Coadministration with strong or moderate CYP3A inducers
- Avoid coadministration
-
If coadministration with moderate CYP3A inducers is unavoidable
- Current pirtobrutinib dose is 200 mg qDay: Increase to 300 mg qDay
- Current pirtobrutinib dose is 50 mg or 100 mg qDay: Increase dose by 50 mg
Renal impairment
- Mild-to-moderate (eGFR 30-89 mL/min): No dosage adjustment necessary
-
Severe (eGFR 15-29 mL/min)
- Current dose is 200 mg qDay: Reduce to 100 mg qDay
- Current dose is 100 mg qDay: Reduce to 50 mg qDay
- Current dose is 50 mg qDay: Discontinue treatment
- Patients on dialysis: Pharmacokinetics are unknown
Hepatic impairment
- All severities: No dosage adjustment necessary
Dosing Considerations
Verify pregnancy status in females of reproductive potential before initiating
Safety and efficacy not established
Studies did not include enough patients with MCL aged <65 years to compare the differences in effect in relation to age
Patients aged ≥65 years experienced higher rates of Grade ≥3 adverse reactions and serious adverse reactions compared with patients aged <65 years
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (0)
Minor (0)
Adverse Effects
>10%
All grades
- Hemoglobin decreased (42%)
- Platelet count decreased (39%)
- Neutrophil count decreased (36%)
- Lymphocyte count decreased (32%)
- Creatinine increased (30%)
- Fatigue (29%)
- Musculoskeletal pain (27%)
- Edema (19%)
- Diarrhea (19%)
- Calcium decreased (19%)
- Dyspnea (17%)
- AST increased (17%)
- Cough (16%)
- Bruising (16%)
- Pneumonia (16%)
- Peripheral neuropathy (14%)
- Rash (14%)
- Fever (13%)
- Constipation (13%)
- Potassium decreased (13%)
- Sodium decreased (13%)
- Lipase increased (12%)
- Arthritis or arthralgia (12%)
- Abdominal pain (11%)
- Nausea (11%)
- Hemorrhage (11%)
- Alkaline phosphatase increased (11%)
- ALT increased (11%)
- Potassium increased (11%)
Grade 3-4
- Neutrophil count decreased (16%)
- Lymphocyte count decreased (15%)
- Pneumonia (14%)
- Platelet count decreased (14%)
1-10%
All grades
- Upper respiratory tract infections (10%)
- Dizziness (10%)
Grade 3-4
- Hemoglobin decreased (9%)
- Lipase increased (4.4%)
- Musculoskeletal pain (3.9%)
- Hemorrhage (3.1%)
- Dyspnea (2.3%)
- Fatigue (1.6%)
- ALT or AST increased (1.6%)
- Creatinine increased (1.6%)
- Calcium decreased (1.6%)
- Potassium decreased (1.6%)
<1%
Grade 3-4
- Edema (0.8%)
- Arthritis or arthralgia (0.8%)
- Abdominal pain (0.8%)
- Upper respiratory tract infections (0.8%)
- Peripheral neuropathy (0.8%)
- Potassium increased (0.8%)
Warnings
Contraindications
None
Cautions
For all adverse reactions, based on severity, reduce dose, temporarily withhold, or permanently discontinue
Grade 3 or 4 cytopenias, including neutropenia, anemia, and thrombocytopenia reported; monitor complete blood cell counts regularly during treatment
Atrial fibrillation and atrial flutter occurred; monitor for signs and symptoms of arrhythmias (eg, palpitations, dizziness, syncope, dyspnea) and manage appropriately
Second primary malignancies, including non-skin carcinomas, developed; advise patients to use sun protection and monitor for development of second primary malignancies
Based on findings in animals, fetal harm may occur when administered to pregnant females
Infections
- Serious and fatal infections (eg, bacterial, viral, or fungal) and opportunistic infection reported
- Consider antimicrobial prophylaxis and vaccinations in patients who are at increased risk for infections
- Monitor for signs and symptoms of infection, evaluate promptly, and treat appropriately
Hemorrhage
- Serious and fatal hemorrhage occurred
- Major hemorrhage occurred at a higher incidence in patients taking pirtobrutinib without antithrombotic agents than in those taking pirtobrutinib with antithrombotic agents (1.7% vs 0.7%)
- Consider the risks and benefits of antithrombotic agents when coadministered with pirtobrutinib
- Monitor for signs of bleeding
- Consider the benefit-risk of withholding pirtobrutinib for 3-7 days pre- and post-surgery depending upon type of surgery and risk of bleeding
Drug interaction overview
- CYP3A4 substrate
- P-gp inhibitor
- Moderate CYP2C8 and BCRP inhibitor
- Weak CYP2C19 and CYP3A inhibitor
-
Strong CYP3A inhibitors
- Avoid coadministration; if unavoidable, reduce pirtobrutinib dose
- Strong CYP3A inhibitors increase pirtobrutinib systemic exposure and risk for adverse reactions
-
Strong or moderate CYP3A inducers
- Avoid coadministration
- If use of moderate CYP3A inducers is unavoidable, increase pirtobrutinib dose
- Strong or moderate CYP3A inducers decrease pirtobrutinib systemic exposure and may reduce pirtobrutinib efficacy
-
Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP substrates
- Pirtobrutinib may increase plasma concentrations of sensitive P-gp, CYP2C8, BCRP, which may increase the risk of adverse reactions related to these substrates
- Refer to prescribing information for sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP substrates for dosing recommendations
Pregnancy & Lactation
Pregnancy
Based on findings from animal studies, fetal harm may cause when administered to pregnant females
No data are available on use in pregnant females to evaluate for a drug-associated risk
Verify pregnancy status in females of reproductive potential before initiating
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 1 week after last dose
Animal data
- Doses ≥375 mg/kg BID caused decreased fetal body weights and increased incidence of malformations and variations in urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (mispositioned ovaries and misshapen uterus), and bone (misshapen sternebrae)
- At 500 mg/kg BID, total resorption observed
- At 375 mg/kg BID in rats, maternal systemic exposures (AUC) were ~3 times the human exposure at 200 mg qDay
- Advise pregnant females of potential risk to a fetus
Lactation
There are no data on drug presence in human milk or the effects on breastfed children or milk production
Advise females not to breastfeed during treatment and for 1 week after last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Bruton tyrosine kinase (BTK) inhibitor
In 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 the C481 mutation, ultimately inhibiting BTK kinase activity
Absorption
Peak plasma concentration (Cmax): 3,670 ng/mL (Cycle 1 Day 8); 6,460 ng/mL (steady-state)
Median peak plasma time (tmax): 2 hr
AUC: 81,800 h⋅ng/mL (Cycle 1 Day 8); 91,300 h⋅ng/mL (steady-state)
Steady-state achieved at 5 days
Accumulation ratio: 1.63
Bioavailability: 85.5%
Effects of food
- High-fat meal: Decreased Cmax by 23% and delayed tmax by 1 hr
Distribution
Vd: 32.8 L
Protein bound: 96%
Mean blood-to-plasma ratio: 0.79
Metabolism
Primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9
Elimination
Half-life: ~19 hr
Clearance: 2.02 L/hr
Excretion: Feces (37% [18% unchanged]); urine (57% [10% unchanged]
Administration
Oral Administration
Take with or without food at the same time each day
Swallow tablets whole with water; do NOT cut, crush, or chew
Missed dose
- Missed dose >12 hr: Do not make up dose and take next dose as scheduled
Storage
Tablets: Store at room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
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