基于细胞水平药效学介导药物处置模型预测晚期或转移性实体瘤患者中GI-102固定剂量给药和基于体重给药的药代动力学和药效学特征

GI-102 (CD80/IL2v3) is designed to direct IL-2 variant to immune cells and tumor cells, and to block CTLA-4 via CD80. Proliferation of cytotoxic T (T c ) cells and natural killer (NK) cells is enhanced through selective binding to IL-2Rbetagamma. CD80-CTLA4 binding further inhibits immunosuppressive function of regulatory T (T reg ) cells. Based on GI-102 monotherapy dose-escalation data of the phase 1/2 first-in-human study (KEYNOTE-G08), a cell-level pharmacodynamics-mediated drug disposition (PDMDD) model was constructed to assess the relationship between drug exposure, target receptor occupancy, and pharmacodynamic (PD) effect. Historically, IL-2 therapies relied on body-weight-based dosing due to narrow therapeutic windows and high interpatient variability. Leveraging GI-102 safety and tolerability in humans, model-informed simulations compared overall pharmacokinetic (PK) and PD profiles of fixed-dose versus weight-based dosing.The model was constructed by simultaneously fitting drug concentrations (n=1185) and total lymphocyte (n=826), T c cell, NK cell, and T reg cell counts (n=529 each) from 54 patients with advanced or metastatic solid tumors who received GI-102 intravenously every three weeks at doses of 0.06-0.45 mg/kg. The target-mediated drug disposition (TMDD) model incorporated time-varying PD-mediated disposition at the cellular level. Lymphocyte diapedesis after treatment was described empirically, and time delay between drug concentrations and lymphocyte increase driven by GI-102-IL-2Rbetagamma stimulation was captured by an indirect response model with the operational model of agonism. Following model diagnostics, Monte-Carlo simulations with 1000 replicates were performed for each scenario using the final model. Modeling was conducted using NONMEM® v7.5.0, and data processing and plotting using R v4.3.3. The two-compartment, cell-level PDMDD model adequately described central tendency of observed PK/PD data. Simulations showed a clear exposure-response relationship across doses. At 0.24-0.45 mg/kg, total lymphocytes and T c cells, accounting for diapedesis, reached levels around 3640-4136 cells/μL and 515-572 cells/μL, respectively. At the same range, NK cells were predicted to exceed 1000 cell/μL, indicating robust expansion at receptor occupancy < 50%. In addition, simulations for fixed-dose regimen of 10, 20, and 30 mg showed increased immune cell proliferation, largely comparable to corresponding weight-based doses of 0.12, 0.24, and 0.35 mg/kg, respectively. Our modeling and simulation provides preliminary prediction of PD effect at tested doses and fixed-dose regimens, serving as reference for determining optimal dose and dosing regimen.