Abstract 3892: Population pharmacokinetics of siltuximab: An analysis across tumor types

Abstract

Abstract Introduction: Siltuximab is an IL-6 inhibiting monoclonal antibody which has been studied in solid tumors and hematologic malignancies, but no comprehensive pharmacokinetic (PK) analysis has been conducted to determine the impact of disease on siltuximab disposition. Methods: Siltuximab pharmacokinetic data from 7 Phase I and II clinical trials included healthy subjects, Castleman’s disease, ovarian cancer, non-Hodgkin’s lymphoma, multiple myeloma, smoldering multiple myeloma, chronic lymphocytic leukemia, renal cell carcinoma, and solid tumors with KRAS mutations. Siltuximab was most commonly dosed at 11 or 15 mg/kg (range 1 - 20 mg/kg) with 70% of patients receiving multiple doses. Plasma samples were obtained 0.33 h - 27 weeks after dosing with siltuximab concentrations determined using a validated ELISA assay. The PK analysis was performed using nonlinear mixed effects modeling (NONMEM 7.3) and included data from 465 subjects (7,761 samples). Results: Siltuximab concentration data was best fit with a two-compartment model. Healthy volunteer status (HV), Castleman’s disease (CD), albumin (ALB), and ALT were independent predictors of clearance (CL), while ALB, HV, serum creatinine (SCR), weight (WT), and smoldering multiple myeloma predicted volume of distribution (Vdss). There was no impact of dose level on CL or Vdss. In the final PK model CL was described as: CL (mL/hr) = 8.93 x (ALB/4.1)-0.843 x (ALT/17)-0.0964 x 1.24 (if HV) x 0.765 (if CV); between subject variability was 41.0%. The final model was used to simulate a dose of 11 mg/kg for 1000 subjects with the median (IQR) exposure (AUC) and CL as follows: CL (mL/hr)AUC (mcg*day/mL)Half-lifeβ (days)Healthy volunteers6.61 (4.99 – 8.63)4,855.8 (3,717.4 - 6,426.3)24.5 (19.2 – 33. 6)Castleman’s Disease11.11 (8.48 - 14.36)2,884.3 (2,233.7 - 3,782.5)19.1 (14.6 - 25.0)Other tumor types9.13 (6.93 - 11.52)3,514.5 (2,786.2 - 4,627.0)22.2 (17.5 - 30.5) Conclusions: This combined population PK analysis demonstrates that clearance can differ with disease type consistent with previously published variations in IL-6 activity. These population differences along with significant between subject variability suggest that clinical and disease factors influence siltuximab disposition and may need to be considered in dosing requirements. Citation Format: Mina Nikanjam, Jin Yang, Edmund V. Capparelli. Population pharmacokinetics of siltuximab: An analysis across tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3892.