Btk Kinase Inhibitor: Pharmacodynamics, Pharmacokinetics and Adverse Events

General Description

Btk Kinase Inhibitor, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, exerts its pharmacodynamics through irreversible covalent binding to BTK Cys-481. It demonstrates remarkable selectivity for BTK and TEC, inhibiting proliferation and inducing apoptosis in B cell lymphoma cell lines. Pharmacokinetics show rapid absorption, high plasma protein binding, and metabolism primarily by CYP3A4 enzymes. Adverse events include infections, skin disorders, myelosuppression, and bleeding, with manageable safety profiles in B cell malignancy trials. Combination therapies exhibit synergistic effects but may increase AEs. Vigilance in monitoring and managing AEs is crucial for optimizing patient outcomes when using Btk Kinase Inhibitor.

Figure 1. Btk Kinase Inhibitor

Pharmacodynamics

Btk Kinase Inhibitor, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, exerts its pharmacodynamics through irreversible covalent binding to BTK Cys-481. In vitro studies reveal its remarkable selectivity for BTK (IC50 of 6.8 nmol/L) and TEC (IC50 of 48 nmol/L) over other kinases, including ITK and human epidermal growth factor 2 receptor (ERBB2). Notably, compared to ibrutinib, Btk Kinase Inhibitor exhibits greater selectivity against off-target enzymes like epidermal growth factor receptor, ITK, and BMX, while maintaining lower selectivity for TEC. Btk Kinase Inhibitor demonstrates significant antitumor activity, inhibiting proliferation and inducing apoptosis in activated B cell-like human diffuse large B cell lymphoma cell lines and suppressing tumor growth in xenograft models. Combination therapy with Btk Kinase Inhibitor and agents like idelalisib, rituximab, or GS-5829 shows synergistic or additive antitumor effects, even partially restoring sensitivity in cells with acquired resistance to idelalisib. Additionally, Btk Kinase Inhibitor inhibits osteoclast differentiation in vitro and suppresses bone loss in mice, suggesting potential therapeutic benefits in bone diseases such as osteoporosis and rheumatoid arthritis. ¹

Pharmacokinetics

Btk Kinase Inhibitor's pharmacokinetics involve rapid absorption, with peak plasma concentrations achieved around 2.87 hours post-administration. When taken orally at 480 mg once daily in a fasted state, Btk Kinase Inhibitor is rapidly absorbed in Japanese patients with primary central nervous system lymphoma (PCNSL). However, administration after a standard meal increases both peak plasma concentrations (Cmax) and the area under the plasma concentration–time curve by 74% and 29%, respectively, necessitating administration 1 hour before or 2 hours after a meal. Btk Kinase Inhibitor exhibits high plasma protein binding (92%) and is predominantly metabolized by CYP3A4 enzymes. Metabolites M33 and M12, along with the unchanged parent drug, account for the majority of plasma radioactivity post-administration. Elimination occurs primarily via feces (52.2%) and urine (42.1%), with a mean elimination half-life of approximately 3.55 hours. Coadministration with CYP3A inhibitors or inducers may alter Btk Kinase Inhibitor exposure, and concurrent use with anticoagulant/antiplatelet agents may increase the risk of bleeding. ²

Adverse Events

Btk Kinase Inhibitor demonstrates a manageable safety profile across various clinical trials in patients with B cell malignancies. The most frequently reported adverse events (AEs) associated with Btk Kinase Inhibitor include infections, severe skin disorders, myelosuppression, interstitial lung disease, bleeding, and liver dysfunction. In monotherapy trials involving patients with primary central nervous system lymphoma (PCNSL) or other B cell malignancies, Btk Kinase Inhibitor was generally well tolerated. Common any-grade AEs included rash, neutropenia, leukopenia, and lymphopenia. Grade ≥ 3 AEs primarily comprised neutropenia, lymphopenia, leukopenia, and erythema multiforme. Additionally, rare instances of grade 5 AEs, such as Pneumocystis jirovecii pneumonia and interstitial lung disease, were reported. Combination therapies involving Btk Kinase Inhibitor with agents like idelalisib or entospletinib exhibited higher rates of treatment-emergent AEs, with serious AEs reported in a significant proportion of patients. Grade 3 or 4 AEs, such as neutropenia and urinary tract infections, were more prevalent in combination therapy settings compared to monotherapy. Overall, while Btk Kinase Inhibitor demonstrates efficacy in treating B cell malignancies, clinicians should remain vigilant for potential AEs, particularly when used in combination regimens. Close monitoring and prompt management of AEs are essential to optimize patient outcomes. ³

Reference

1. Liclican A, Serafini L, Xing W, et al. Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton’s tyrosine kinase reveals differences in on- and off- target inhibition. Biochim Biophys Acta Gen Subj. 2020; 1864(4): 129531.

2. Ono Pharmaceutical Co. VELEXBRUⓇ (Tirabrutinib) 80 mg tablets: Japanese prescribing information. 2020.

3. Nagane M, Narita Y, Mishima K, et al. Phase 1/2 study of tirabrutinib (ONO/GS-4059), a next-generation bruton’s tyrosine kinase (BTK) inhibitor, monotherapy in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL). Blood. 2019; 134(Suppl 1).

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