Pirtobrutinib (Jaypirca™)

What is pirtobrutinib? Pirtobrutinib is a reversible Bruton tyrosine kinase (BTK) inhibitor that blocks signaling of B-cell antigen receptor and cytokine pathway signaling protein, which are essential for B-cell proliferation and functionality. Pirtobrutinib binds to both wild-type BTK and BTK with C481 mutations. What is pirtobrutinib approved for? Pirtobrutinib is approved for adults with relapsed or refractory mantle cell lymphoma after at least two lines of prior systemic therapy, which includes a BTK inhibitor. What is the basis for this approval? Pirtobrutinib was approved under an accelerated approval by the FDA based on results of the BRUIN study. This was a Phase I/II open-label, single-arm, multicenter study that evaluated 120 patients with mantle cell lymphoma that had previously received treatment with a BTK inhibitor (Lancet 2021; doi: 10.1016/S0140-6736(21)00224-5). The most common previously used BTK inhibitors included ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%). Overall, 60 patients (50%) had a response to pirtobrutinib 200 mg once daily with 15 patients (13%) having a complete response and 45 patients (38%) having a partial response. The median duration of therapy was 8.3 months (95% CI: 5.7, NE). How do you administer this drug? Pirtobrutinib is administered at 200 mg by mouth once daily at the same time each day until disease progression or unacceptable toxicity. Patients are instructed to swallow the tablets whole with water and the tablets should not be cut, crushed, or chewed. Pirtobrutinib can be taken with or without food. Pirtobrutinib is available in 50 mg and 100 mg tablets. What are the common side effects associated with pirtobrutinib (>20%)? Common side effects of pirtobrutinib include fatigue, musculoskeletal pain, anemia, thrombocytopenia, neutropenia, lymphocyte count decrease, and serum creatinine increase. Another common side effect is temporary lymphocytosis, which occurs within 1-2 weeks from initiation of therapy and lasted a median duration of 11 weeks in the BRUIN trial. What are the uncommon side effects associated with pirtobrutinib (<10%)? Uncommon but clinically relevant side effects of pirtobrutinib include hemorrhage, dizziness, pleural effusion, tumor lysis syndrome, upper respiratory tract infection, headache, urinary tract infections, memory impairment, and visual disturbances. Other adverse events that do not have a defined frequency include atrial fibrillation, secondary primary malignancies, and opportunistic infections. Are there any important drug interactions I should be aware of? Pirtobrutinib is a CYP3A substrate; therefore, it does have clinically relevant drug interactions. The use of strong CYP3A inhibitors with pirtobrutinib is expected to increase the AUC of pirtobrutinib by approximately 49 percent, putting patients at a greater risk for adverse effects. Strong CYP3A inhibitors should be avoided concurrently with pirtobrutinib. If the use of a strong CYP3A inhibitor cannot be avoided, the dose of pirtobrutinib should be reduced by 50 mg once daily. If the patient is already taking 50 mg once daily, pirtobrutinib should be held until the discontinuation of the CYP3A inhibitor and 5 half-lives after before resumption of therapy. The use of a strong or moderate CYP3A inducer is expected to decrease the AUC of pirtobrutinib by approximately 71 percent and 27-49 percent, respectively. Strong or moderate CYP3A inducers should be avoided concurrently with pirtobrutinib. If the use of a moderate CYP3A inducer is necessary and the dose of pirtobrutinib is 200 mg once daily, the dose should be increased to 300 mg once daily. If the dose of pirtobrutinib is 50 or 100 mg once daily, the dose should be increased by 50 mg if taken with a moderate CYP3A inducer. Pirtobrutinib is also a P-gp inhibitor, a moderate CYP2C8 and BCRP inhibitor, and a weak CYP2C19 and CYP3A inhibitor. Providers are urged to utilize recommendations in approved product labeling to determine dosing strategies while using these substrates with pirtobrutinib. How do I adjust the dose in the setting of renal or hepatic insufficiency? Dose adjustments are required for patients with severe renal impairment (eGFR 15-29 mL/min). In the setting of severe renal impairment, pirtobrutinib should be reduced to 100 mg once daily if the patient is taking 200 mg once daily. If the patient is taking a dose different than 200 mg once daily, the dose should be reduced by 50 mg once daily. If the patient is already taking 50 mg once daily, pirtobrutinib should be discontinued. No dosage adjustment is necessary for patients with hepatic impairment. What should my patients know about pirtobrutinib? Pirtobrutinib is the first reversible BTK inhibitor, so it can be used even if they are showing signs of progression on a second-line BTK inhibitor. Patients who could become pregnant should use contraception while taking pirtobrutinib and for 1 week after their last dose of pirtobrutinib. Patients may be asked to hold their pirtobrutinib for 3-7 days prior to and after surgery depending on their risk of bleeding from the procedure. What useful links are available regarding pirtobrutinib? Indication and safety information: https://bit.ly/3ALWGQV FDA approval: https://bit.ly/3Vrq1cR Any ongoing clinical trials related to pirtobrutinib? Pirtobrutinib is being studied for the treatment of WaldenstrÖm macroglobulinemia, treatment-naïve chronic lymphocytic leukemia, and previously treated chronic lymphocytic leukemia. More information about these trials is available at clinicaltrials.gov. MIKAELA MCCABE, PHARMD, is PGY2 Oncology Resident at Barnes-Jewish Hospital in St. Louis, MO. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/Manager, Clinical Pharmacy Services at Washington University School of Medicine. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.Mikaela McCabe, PharmD: Mikaela McCabe, PharmDJanelle E. Mann, PharmD, BCOP: Janelle E. Mann, PharmD, BCOPRamaswamy Govindan, MD: Ramaswamy Govindan, MD