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Background and Objective <p>Navitoclax, an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor, inhibits antiapoptotic Bcl-2 family proteins (with high affinity to Bcl-XL, Bcl-2, and Bcl-W). Navitoclax in combination with ruxolitinib has been investigated&#xa0;to treat patients with myelofibrosis (MF).</p> Methods <p>Since navitoclax undergoes hepatic metabolism, we evaluated the pharmacokinetics (PK) and safety of single-dose navitoclax 50&#xa0;mg in a phase 1 study in participants with mild (<i>N</i> = 6), moderate (<i>N</i> = 6), or severe (<i>N</i> = 1) hepatic impairment and matched participants with normal hepatic function (<i>N</i> = 7). All participants in this study were enrolled per Child–Pugh classification, with demographics matched per age, weight, and race.</p> Results <p>Navitoclax maximum plasma concentration (<i>C</i><sub>max</sub>), area under the plasma concentration–time curve for time zero to infinity (AUC<sub>0-∞</sub>), and terminal elimination half-life (t<sub>1/2</sub>)&#xa0;in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in C<sub>max</sub> and AUC<sub>0–∞</sub> values in participants with mild and moderate hepatic impairment were within 25% of normal hepatic function.&#xa0;Overall, 2/20 (10%) participants receiving a 50 mg single dose reported grade 1 treatment-emergent adverse events of nausea (<i>N</i> = 1) and diarrhea (<i>N</i> = 1).</p> Conclusions <p>In summary, no new safety issues were identified. On the basis of the pharmacokinetic results, no dose adjustment is required for patients with MF with mild or moderate hepatic impairment.</p>

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Pharmacokinetics and Safety of Navitoclax in Hepatic Impairment

  • 期刊论文

  • 发表日期：

    2025年3月27日

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  • Maulik Patel,
  • Jalaja Potluri,
  • Thomas Marbury,
  • Eric Lawitz,
  • Juan Carlos Rondon,
  • David M. Hoffman,
  • Satya R. Siddani,
  • Kennan C. Marsh,
  • Elaine J. Kim,
  • Muhammad Erfan Uddin,
  • Rajeev M. Menon,
  • Akshanth R. Polepally

摘要

Background and Objective

Navitoclax, an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor, inhibits antiapoptotic Bcl-2 family proteins (with high affinity to Bcl-XL, Bcl-2, and Bcl-W). Navitoclax in combination with ruxolitinib has been investigated to treat patients with myelofibrosis (MF).

Methods

Since navitoclax undergoes hepatic metabolism, we evaluated the pharmacokinetics (PK) and safety of single-dose navitoclax 50 mg in a phase 1 study in participants with mild (N = 6), moderate (N = 6), or severe (N = 1) hepatic impairment and matched participants with normal hepatic function (N = 7). All participants in this study were enrolled per Child–Pugh classification, with demographics matched per age, weight, and race.

Results

Navitoclax maximum plasma concentration (Cmax), area under the plasma concentration–time curve for time zero to infinity (AUC0-∞), and terminal elimination half-life (t1/2) in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in Cmax and AUC0–∞ values in participants with mild and moderate hepatic impairment were within 25% of normal hepatic function. Overall, 2/20 (10%) participants receiving a 50 mg single dose reported grade 1 treatment-emergent adverse events of nausea (N = 1) and diarrhea (N = 1).

Conclusions

In summary, no new safety issues were identified. On the basis of the pharmacokinetic results, no dose adjustment is required for patients with MF with mild or moderate hepatic impairment.