Pharmacokinetics and Safety of Navitoclax in Hepatic Impairment.

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.