083: Pharmacokinetics & Safety of Navitoclax in Hepatic Impairment

Statement of Purpose: Navitoclax is an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor that binds and inhibits antiapoptotic Bcl-2 family proteins with high affinity to Bcl-XL, Bcl-2, and Bcl-W and is currently being developed for the treatment of myelofibrosis (MF). Navitoclax undergoes hepatic metabolism. Therefore, the purpose of this study was to evaluate the pharmacokinetics (PK) and safety of navitoclax in subjects with mild, moderate, or severe hepatic impairment.

Description of Methods & Materials: This Phase I study was carried out in females with hepatic impairment without myelofibrosis or other comorbidities. Subjects were enrolled per Child-Pugh classification of mild, moderate (n=6 each), and severe hepatic impairment (n=1, planned enrollment of 6), and normal hepatic function subjects (n=6) demographic matched per age, weight, and race. All subjects received a single 50 mg dose of navitoclax with a low-fat meal. Blood samples for navitoclax and its metabolite (M13) were collected up to 216 h after navitoclax administration. Blood samples for determining the unbound fraction of navitoclax were collected and assayed. Individual PK parameters were calculated using non-compartmental analysis in Phoenix WinNonlin v8.2.

Data & Results: Navitoclax maximum observed plasma concentration (C_max) and area under the plasma concentration-time curve for time zero to infinity (AUC_inf) in patients with mild or moderate hepatic impairment were similar to subjects with normal hepatic function (Table 1). The AUC_inf and terminal elimination half-life (t_1/2) in subjects with mild and moderate impairment were comparable to subjects with no impairment. Navitoclax metabolite (M13) was not quantifiable across all cohorts. The unbound fractions of navitoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. In totality, 2/20 (10%) subjects reported Grade 1 treatment emergent adverse events of nausea (n=1) and diarrhea (n=1). No new safety issues were identified from this study.

Interpretation, Conclusion or Significance: Navitoclax C_max and AUC_inf in subjects with mild or moderate hepatic impairment were comparable ( < 25% increase) to subjects with normal hepatic function. Hence, no navitoclax starting dose adjustment is required for subjects with mild or moderate hepatic impairment. Hepatic impairment did not have any impact on unbound fraction of navitoclax. Impact of severe hepatic impairment on the pharmacokinetics of navitoclax could not be fully evaluated at this stage due to limited data.

Disclosures: This study was funded by AbbVie. AbbVie contributed to the research, and interpretation of data, writing, reviewing and approving the publication. All authors are AbbVie employees and may hold AbbVie stocks or options. TM is an employee and equity owner of Orlando Clinical Research Center. EL and CR have no COI disclosures.