Rilzabrutinib, a reversible covalent Bruton's tyrosine kinase inhibitor: Absorption, metabolism, excretion, and absolute bioavailability in healthy participants

Ucpinar, Sibel; Smith, Patrick F.; Li, Long; Li, Fujun; Yan, Hui; Wadhwa, Jyoti; Chu, Katherine A; Shu, Jin; Nunn, Philip A.; Li, Mengyao

doi:10.1111/cts.13524

Cited by 8 publications

(2 citation statements)

References 16 publications

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“…Rilzabrutinib, a reversible covalent Bruton's tyrosine kinase (BTK) inhibitor, has promising potential in immune thrombocytopenia [54]. Its slow dissociation from BTK results in a prolonged duration of action, leading to a sustained target occupancy that helps minimize the adverse reactions caused by off-target nonspecific binding [55].…”

Section: Covalent Inhibitorsmentioning

confidence: 99%

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

Li,

Gong,

Zhou

et al. 2024

IJMS

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Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood–brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.

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Section: Covalent Inhibitorsmentioning

confidence: 99%

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

Li,

Gong,

Zhou

et al. 2024

IJMS

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“…Remarkably, bortezomib, a proteasome inhibitor, has showcased success in treating IgG4-RD. This innovative approach has been validated, with case reports highlighting its efficacy, particularly in patients grappling with IgG4-RD lung involvement combined with periorbital inflammatory pseudotumor ( 90 ).…”

Section: Treatment Of Igg4-dsdmentioning

confidence: 99%

IgG4-related digestive diseases: diagnosis and treatment

Wu,

Wang

2023

Front. Immunol.

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IgG4-related digestive diseases encompass a group of chronic inflammatory disorders characterized by autoimmune reactions and fibrosis affecting multiple digestive organs. These diseases are identified by elevated serum levels of IgG4 and the presence of IgG4-positive plasma cell infiltration in the affected sites, along with storiform fibrosis, obliterative phlebitis, and eosinophilic infiltration. Although extensive research has been conducted, a comprehensive understanding of these conditions remains elusive. Current clinical diagnosis often relies on the application of integrated diagnostic criteria for IgG4-related diseases, combined with specific organ involvement criteria. Distinguishing them from malignancies poses considerable challenges. Moreover, further investigations are required to elucidate the underlying pathogenic mechanisms and explore potential therapeutic interventions. This review provides a systematic classification of IgG4-related digestive diseases while discussing their diagnostic strategies, clinical presentations, and treatment modalities. The comprehensive insights shared herein aim to guide clinicians in their practice and contribute to the advancement of knowledge in this field.

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Effects of Quinidine or Rifampin Co‐administration on the Single‐Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants

Rask‐Madsen,

Katragadda,

et al. 2024

Clinical Pharm in Drug Dev

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This open‐label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug‐drug interaction between rilzabrutinib and quinidine (an inhibitor of P‐glycoprotein [P‐gp] and CYP2D6) or rifampin (an inducer of CYP3A and P‐gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400 mg administered on day 1 and again, following a wash‐out period, after co‐administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300 mg every 8 hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600 mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0‐∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P‐gp.

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Rilzabrutinib, a reversible covalent Bruton's tyrosine kinase inhibitor: Absorption, metabolism, excretion, and absolute bioavailability in healthy participants

Cited by 8 publications

References 16 publications

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

IgG4-related digestive diseases: diagnosis and treatment

Effects of Quinidine or Rifampin Co‐administration on the Single‐Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants

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