Semi-Mechanistic PK/PD Modeling of Platelets and Spleen Volume With Navitoclax in Combination With Ruxolitinib in...

Navitoclax, an oral small molecule BCL-X_L/BCL-2 inhibitor evaluated in myelofibrosis, was assessed through integrated PK/PD modeling to guide starting dose and dose-reduction decisions when combined with ruxolitinib. An integrated sequential PK/PD model was developed to describe the relationships between navitoclax and ruxolitinib exposure, platelet count, and spleen volume. Simulations were conducted to assess spleen volume reductions of ≥ 35% at week 24 (SVR_35W24) and incidences of ≥ grade 3 or grade 4 thrombocytopenia. The population PKs were adequately characterized by two-compartment models, and the subsequent integrated PK/PD model adequately described the platelet and spleen volume data. Model simulations indicated that the incidence of ≥ grade 3 or grade 4 thrombocytopenia during a weekly ramp-up from navitoclax 100 to 200 mg once daily (QD) was similar to that predicted with a flat 200 mg QD starting dose. Simulations suggested that reducing doses of navitoclax by 25 mg for patients with baseline platelet counts ≤ 150 × 10⁹/L (starting at 100 mg) and by 50 mg, with an additional 25 mg if needed, for those > 150 × 10⁹/L (starting at 200 mg) effectively minimized ≥ grade 3 thrombocytopenia while maintaining SVR_35W24. Integrated PK/PD model simulations suggested that a flat starting dose of navitoclax 200 mg for baseline platelets > 150 × 10⁹/L, and 100 mg for ≤ 150 × 10⁹/L with ruxolitinib minimized thrombocytopenia risk while maintaining efficacy. Dose reductions of 25 mg for the 100 mg start and 50 mg (plus 25 mg if needed) for the 200 mg start optimized the benefit-risk balance.