Pharmacokinetics and Safety of Navitoclax in Hepatic Impairment.

in Clinical pharmacokinetics by 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

TLDR

  • Navitoclax, a Bcl-2 family protein inhibitor, exhibited comparable pharmacokinetics and safety in patients with mild, moderate, or normal hepatic function.

Abstract

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). 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. Navitoclax maximum plasma concentration (C), area under the plasma concentration-time curve for time zero to infinity (AUC), and terminal elimination half-life (t) in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in Cand AUCvalues 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). 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.

Overview

  • The study evaluated the pharmacokinetics and safety of single-dose navitoclax 50 mg in patients with mild, moderate, or severe hepatic impairment compared to those with normal hepatic function.
  • The study aimed to determine whether navitoclax requires dose adjustment in patients with myelofibrosis (MF) and mild or moderate hepatic impairment.
  • The study enrolled participants with matched demographics (age, weight, and race) and hepatic impairment classification per Child-Pugh criteria.

Comparative Analysis & Findings

  • The maximum plasma concentration (C), area under the plasma concentration-time curve for time zero to infinity (AUC), and terminal elimination half-life (t) in participants with mild or moderate hepatic impairment were comparable to those with normal hepatic function.
  • The percentage change in C and AUC values in participants with mild and moderate hepatic impairment was within 25% of normal hepatic function.
  • Overall, 2/20 (10%) participants reported grade 1 treatment-emergent adverse events of nausea and diarrhea, with no new safety issues identified.

Implications and Future Directions

  • The study suggests that navitoclax requires no dose adjustment for patients with MF and mild or moderate hepatic impairment, based on the pharmacokinetic results.
  • Further studies are needed to investigate the safety and efficacy of navitoclax in patients with severe hepatic impairment.
  • The combination of navitoclax and ruxolitinib for the treatment of MF should be further evaluated in clinical trials.
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