Sr. Research Specialist Regeneron Pharmaceuticals, Inc. Cardiff By The Sea, California, United States
Background: Odronextamab is a hinge-stabilized, human, CD20xCD3 IgG4 bispecific monoclonal antibody under clinical development for the treatment of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). A non-linear mixed-effects modeling analysis was performed to describe the pharmacokinetics (PK) of odronextamab along with its sources of variability, including the influence of intrinsic and extrinsic factors. Methods: A total of 507 patients with R/R B-NHL received odronextamab as monotherapy in the open-label studies NCT02290951 (ELM-1; N=167) or NCT03888105 (ELM-2; N=340) and had at least one non-missing post-baseline concentration of odronextamab in serum. Concentrations in serum were determined using validated enzyme-linked immunosorbent assays with a lower limit of quantitation of 0.00313 mg/L. Concentration-time profiles over a dose range of 0.03 mg to 320 mg following intravenous infusion were described by a two-compartment model characterized by parallel linear (first-order) and non-linear (Michaelis-Menten) elimination processes. The Michaelis-Menten elimination included a time-dependent component. Results: The developed PK model described the observed odronextamab concentration-time profiles well, regardless of B-NHL subtype. The population estimates of linear clearance (CL) and volume of distribution at steady state (V) were 0.19 L/day and 9.4 L, respectively. The median target-mediated clearance before treatment was approximately 5 L/day. An empirical function describing a decline in Vmax over time improved fitting of the observed data, with baseline total lymphocyte count being a predictor of baseline Vmax. With the largest effect on odronextamab exposure, baseline body weight was directly correlated with CL and V; albumin was inversely correlated with CL and V, and baseline interleukin-10 was inversely correlated with CL. Conclusion: A reduction of the target-mediated clearance over time above and beyond its association with concentration suggests a reduction in target abundance. This is consistent with the treatment-induced depletion of B cells observed in a limited set of patients where assessments of B-cell counts in serum were available.
