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Purpose <p>While zanubrutinib, a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, is known for its improved target selectivity, a systematic integration of its clinical pharmacology with efficacy and safety across diverse B-cell lymphomas - particularly highlighting its distinct pharmacokinetic and pharmacodynamic profile relative to other BTK inhibitors - is lacking. This review comprehensively summarizes zanubrutinib’s pharmacological characteristics, clinical trial and real-world outcomes, and adverse event management strategies, aiming to provide a clinically actionable resource for optimized and individualized therapy.</p> Methods <p>We conducted a structured literature search in PubMed, Embase, Cochrane Library, and Web of Science using keywords including “zanubrutinib,” “BGB-3111,” “BTK inhibitor,” and “B-cell lymphoma.” Relevant publications were critically reviewed to synthesize evidence on zanubrutinib’s pharmacokinetics, pharmacodynamics, clinical efficacy across indications, and management of adverse events, with an emphasis on mechanistic insights and practical clinical guidance.</p> Results <p>Zanubrutinib demonstrates a favorable efficacy and safety profile supported by its distinct pharmacological characteristics. Its favorable pharmacokinetics include high central nervous system penetration and well-characterized metabolic pathways. Clinically, it induces deep and durable responses across multiple B-cell malignancies, supported by sustained <i>BTK</i> occupancy and a superior free-drug trough concentration relative to its half-inhibitory concentration (IC50). The safety profile is characterized by lower incidences of certain off-target toxicities (e.g., atrial fibrillation) compared to ibrutinib, though infections, bleeding, and cytopenias require vigilant management. Analysis of resistance mechanisms underscores the central role of <i>BTK</i> mutations (e.g., C481S, L528W), informing future therapeutic sequencing.</p> Conclusion <p>This review underscores the value of a pharmacology-guided approach to maximizing zanubrutinib’s benefits, encompassing rational dosing, proactive toxicity management, and strategic positioning within the BTK inhibitor landscape. Future directions should prioritize combinatorial strategies to overcome resistance and therapeutic drug monitoring for precision dosing.</p> Graphical Abstract <p></p>

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Zanubrutinib in B-cell lymphomas: from clinical pharmacology to therapeutic application

  • 期刊论文

  • 发表日期：

    2026年1月19日

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  • Tian-Bo Chen,
  • Yu-Ting Yan,
  • Lu-Ning Sun,
  • Yu-Jiao Guo,
  • Yong-Qing Wang

摘要

Purpose

While zanubrutinib, a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, is known for its improved target selectivity, a systematic integration of its clinical pharmacology with efficacy and safety across diverse B-cell lymphomas - particularly highlighting its distinct pharmacokinetic and pharmacodynamic profile relative to other BTK inhibitors - is lacking. This review comprehensively summarizes zanubrutinib’s pharmacological characteristics, clinical trial and real-world outcomes, and adverse event management strategies, aiming to provide a clinically actionable resource for optimized and individualized therapy.

Methods

We conducted a structured literature search in PubMed, Embase, Cochrane Library, and Web of Science using keywords including “zanubrutinib,” “BGB-3111,” “BTK inhibitor,” and “B-cell lymphoma.” Relevant publications were critically reviewed to synthesize evidence on zanubrutinib’s pharmacokinetics, pharmacodynamics, clinical efficacy across indications, and management of adverse events, with an emphasis on mechanistic insights and practical clinical guidance.

Results

Zanubrutinib demonstrates a favorable efficacy and safety profile supported by its distinct pharmacological characteristics. Its favorable pharmacokinetics include high central nervous system penetration and well-characterized metabolic pathways. Clinically, it induces deep and durable responses across multiple B-cell malignancies, supported by sustained BTK occupancy and a superior free-drug trough concentration relative to its half-inhibitory concentration (IC50). The safety profile is characterized by lower incidences of certain off-target toxicities (e.g., atrial fibrillation) compared to ibrutinib, though infections, bleeding, and cytopenias require vigilant management. Analysis of resistance mechanisms underscores the central role of BTK mutations (e.g., C481S, L528W), informing future therapeutic sequencing.

Conclusion

This review underscores the value of a pharmacology-guided approach to maximizing zanubrutinib’s benefits, encompassing rational dosing, proactive toxicity management, and strategic positioning within the BTK inhibitor landscape. Future directions should prioritize combinatorial strategies to overcome resistance and therapeutic drug monitoring for precision dosing.

Graphical Abstract