Clinical pharmacokinetics and neutropenia-related pharmacodynamics of BAL0891 in patients with solid tumors.

Abstract

e15161 Background: BAL0891 is a dual TTK and PLK1 inhibitor, and its pharmacokinetic (PK) and neutropenia-related pharmacodynamic (PD) characteristics were evaluated using data from a Phase I study. Regimen A of Substudy 1, which involved monotherapy administration in patients with solid tumors using a 3-week cycle with consecutive weekly dosing during the first two weeks, has been completed. Plasma concentration and absolute neutrophil count (ANC) data were collected through Cycle 4. Methods: Full PK sampling was performed on Day 1 and Day 8 of Cycles 1 and 2, with sparse sampling in subsequent Cycles. Blood samples for plasma concentration measurements were generally collected pre-dose and at multiple time points up to 167 hours after the end of the 1-hour infusion. ANC data were collected at protocol-specified time points, with additional measurements obtained at the discretion of the treating physician in patients with suspected or confirmed neutropenia. Cycle 1 data, least affected by patient-related factors such as G-CSF use, were used for mixed-effects modeling. The final dataset comprised 1,000 plasma concentration records and 340 ANC records from 41 patients. Data were analyzed using NONMEM (Version 7.5, ICON plc, Gaithersburg, MA, USA), applying the FOCE-I method where applicable. Models were compared by visual diagnostics and numerical criteria, including the objective function value and the Akaike Information Criterion. Results: BAL0891 exhibited linear PK that was well described by a two-compartment model. Systemic clearance and central volume were estimated at 22.7 L/h and 252 L, respectively, with a model-predicted terminal half-life of approximately 34.3 hours. Dose level was not identified as a significant covariate, and PK parameters were consistent across Cycles and Days. ANC PD were described using a semi-mechanistic turnover model in which plasma concentration inhibited neutrophil production via an E max function. Using this model, the exposure levels associated with an approximately 25% incidence of Grade 3 and Grade 4 neutropenia during Cycle 1 were estimated, corresponding to increasing dose levels. Conclusions: In patients with solid tumors, BAL0891 demonstrated linear and dose-proportional pharmacokinetics. Model-based simulations predict that repeated dosing will result in consistent plasma exposure, with no evidence of clinically relevant inter-occasional variability. Model-based simulations did not predict substantial accumulation with weekly administration. Neutropenia risk was quantitatively described in a dose-dependent manner, enabling characterization of the exposure–toxicity relationship. Clinical trial information: NCT05768932 .