Pharmacokinetics and Safety of Navitoclax in Hepatic Impairment.

Abstract

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 (C_max), area under the plasma concentration-time curve for time zero to infinity (AUC_0-∞), and terminal elimination half-life (t_1/2) in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in C_max and AUC_0-∞ 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.