Population Pharmacokinetics of Epcoritamab Following Subcutaneous Administration in Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.

Background and Objectives: Epcoritamab is a CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL) after ≥ 2 lines of systemic therapy. Here we report the first results from a population pharmacokinetic model-based analysis using data from 2 phase 1/2 clinical trials (EPCORE ^® NHL-1, NCT03625037 and EPCORE NHL-3, NCT04542824) evaluating epcoritamab in patients with R/R B-NHL.
Methods: Plasma concentration-time data included 6819 quantifiable pharmacokinetic samples from 327 patients with R/R B-NHL. A wide range of subcutaneous epcoritamab doses, 0.004-60 mg, was explored, with most patients (n = 298) following the approved dosing regimen: step-up dose (SUD) 1 of 0.16 mg on cycle 1 day 1 and SUD 2 of 0.8 mg on cycle 1 day 8, followed by a full dose of 48 mg administered weekly during cycles 1-3, biweekly in cycles 4-9, and every 4 weeks thereafter. Each cycle lasted 28 days. The data were analyzed using nonlinear mixed-effects modeling.
Results: Quasisteady-state approximation of a two-compartment target-mediated drug disposition model with first-order absorption adequately characterized pharmacokinetics of epcoritamab following subcutaneous administration. After the first full dose and at the end of the weekly dosing regimen (end of cycle 3), the estimated median time to maximum concentration (t _max ) was 4 and 2.3 days, respectively. Age and body weight were significant covariates on the pharmacokinetics of epcoritamab. The geometric mean (coefficient of variation [CV], %) of the apparent total volume of distribution was 25.6 L (82%) for patients with R/R large B cell lymphoma in EPCORE NHL-1. Epcoritamab elimination exhibited nonlinear characteristics, with exposure increasing more than proportionally over 1.5-48 mg doses. The geometric mean (CV%) values of apparent total clearance and terminal half-life were 0.53 L/day (40%) and 22 days (58%), respectively, at the end of cycle 3 for the 48 mg full dose. Clinical data analyses did not identify any association between assessed characteristics, including body weight or age, and clinical efficacy or safety. After accounting for body weight, no clinically significant differences in epcoritamab pharmacokinetics were observed for sex, race, renal or hepatic function, or other disease characteristics. Age was not found to significantly affect epcoritamab pharmacokinetic exposure. Antidrug antibodies developed in 4 (2.6%) of 156 evaluable patients treated with the approved 0.16/0.8/48 mg regimen. Antidrug antibody status did not affect epcoritamab pharmacokinetics.
Conclusions: Epcoritamab pharmacokinetics in R/R B-NHL were well characterized by the population pharmacokinetic model. No dosage adjustments are recommended in subpopulations based on body weight, age, sex, race, mild-to-moderate renal impairment, or mild hepatic impairment. The risk of immunogenicity was low. These are the first published results of population pharmacokinetic modeling for epcoritamab.
Competing Interests: Declarations. Funding: This study was funded by Genmab A/S and AbbVie. Conflict of interest: T.L., M.v.d.L., K.S., M.P., M.S., H.F., T.A., M.G., and S.X. are employees of Genmab. T.A. owns stock in Genmab. L.G. is an employee of QuantPharm LLC and is a paid consultant of Genmab. A.P. is an employee and stockholder of AbbVie. Availability of data and material: Deidentified individual participant data will not be available upon request for further analyses by external independent researchers. Aggregated clinical trial data from the trials are provided via publicly accessible study registries/databases as required by law. For more information, please contact clinicaltrials@genmab.com. Ethics approval: Both EPCORE NHL-1 and EPCORE NHL-3 protocols were approved by an institutional ethics committee before the start of the trials. The trials were conducted in compliance with the International Council for Harmonisation Good Clinical Practice E6(R2) guidelines, local guidelines (Japan Good Clinical Practice for EPCORE NHL-3), principles of the Declaration of Helsinki, and relevant regulatory requirements. Consent to participate: All patients reviewed and signed informed consent forms before enrollment. Consent for publication: Because of the nature of this study, consent to publish was waived. Author contributions: Conceptualization: T.L., A.P., M.G., and S.X. Methodology: T.L., L.G., and M.v.d.L. Formal analysis and investigation: T.L., L.G., M.v.d.L, M.S., and H.F. Writing, original draft preparation: T.L. and S.X. Funding acquisition: T.L. and M.G. Resources: K.S. and M.P. Supervision: T.L., M.G., and S.X. All authors participated in the critical review and revision of this manuscript and provided approval of the manuscript for submission. Code availability: Not applicable.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)