Population Pharmacokinetics and Exposure-Response Analysis of Birociclib Plus Fulvestrant in Advanced Breast Cancer Patients
Authors: Shi Yufei , Wang Li , Xu Nuo , Xu Lingmei , Yang Wenyu , Liu Mingming , Xiang Xiaoqiang , Wang Shuya , Zhu Xiao 
Published: February 2025

Objectives: Birociclib (XZP-3287) is a novel inhibitor of CDK4/6 being developed for the treatment of hormone receptor positive human epidermal growth factor receptor 2 Negative (HR+/HER2-) advanced breast cancer (BC). The objectives were to characterize birociclib and its major active metabolites (XZP-3584 and XZP-5736) population pharmacokinetic (PPK) behavior, and to explore the exposure-response (ER) relationship of birociclib plus fulvestrant. Methods: Data from a phase 3 study in patients with HR+/HER2- advanced BC, phase 1/2 studies primarily in patients with BC, with only 10 non-BC solid tumor patients, and phase 1 food effect and DDI studies in healthy adults were pooled for analysis. Doses of birociclib ranged from 20mg to 560mg QD and 240mg to 480mg BID. Nonlinear mixed-effects modeling using FOCE-I algorithm was performed in NONMEM v7.5. Covariate model was developed via a stepwise approach and its impact on PK metrics was assessed via forest plot. Efficacy endpoints were objective response rate and progression-free survival. Safety endpoints were neutropenia, diarrhea, and blood creatinine (Cr) increased.Results: The PPK analysis incorporated 17520 plasma concentrations (XZP-3287: 5992; XZP-3584: 5764; XZP-5736: 5764) from 407 subjects. Pharmacokinetics (PK) of birociclib, XZP-3584, or XZP-5736 were adequately described by a two-compartment model with absorption lag time and time-dependent relative bioavailability (F). Birociclib's steady-state F decreased by 39.4%, with a rate constant of 0.0026/h. Patient demographics did not contribute to PK variability. When used with strong CYP3A4 inhibitors/inducers, birociclib's clearance and systemic exposure were significantly affected, requiring to avoid concomitant use. The combination with fulvestrant did not show a clinically relevant effect on exposure. Baseline Cr clearance (CrCL) and clearance of XZP-3584 and XZP-5736 had a positive correlation, but the effect in the studied population (CrCL 40-213 mL/min) was not clinically relevant. Therefore, no dose adjustment was required for mild renal impairment. When in combination with fulvestrant, no significant dose/exposure-efficacy relationship was observed for birociclib within the daily dose range of 480 to 720 mg. Higher doses were associated with higher incidence of ≥grade 3 neutropenia (p < 0.001), ≥grade 2 blood Cr increased (p=0.00313), and ≥grade 3 diarrhea (p=0.0012). Risks of ≥ grade 2 blood Cr increased (p < 0.001)  and ≥ grade 3 neutropenia (p=0.0371) were positively correlated with XZP-3584 average daily exposure. No significant ER relationship was observed for ≥ grade 3 diarrhea.Conclusions: The PPK model successfully described birociclib and its metabolites’ PK profile. No dose adjustments were needed based on demographic differences. Birociclib at 360mg BID plus fulvestrant exhibited good efficacy if tolerable. In cases of drug intolerance, birociclib dose reduction may be considered, with limited impact on efficacy.Citations: [None]