Population pharmacokinetics and CD20 binding dynamics for mosunetuzumab in relapsed/refractory B‐cell non‐Hodgkin lymphoma

Mosunetuzumab (Mosun) is a CD20xCD3 T‐cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step‐up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokine...

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Veröffentlicht in:Clinical and translational science Jg. 17; H. 6; S. e13825 - n/a
Hauptverfasser: Bender, Brendan, Li, Chi‐Chung, Marchand, Mathilde, Turner, David C., Li, Feifei, Vadhavkar, Shweta, Wang, Bei, Deng, Rong, Lu, James, Jin, Jin, Li, Chunze, Yin, Shen, Wei, Michael, Chanu, Pascal
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States John Wiley & Sons, Inc 01.06.2024
John Wiley and Sons Inc
Wiley
Schlagworte:
Adult
Aged
Aged, 80 and over
Antibodies, Bispecific - administration & dosage
Antibodies, Bispecific - immunology
Antibodies, Bispecific - pharmacokinetics
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - pharmacokinetics
Antigens, CD20 - immunology
Antigens, CD20 - metabolism
Antineoplastic Agents, Immunological - administration & dosage
Antineoplastic Agents, Immunological - pharmacokinetics
Antineoplastic Agents, Immunological - therapeutic use
Bispecific antibodies
Body weight
CD20 antigen
Dosage
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug dosages
Female
Humans
Immunotherapy
Lymphocytes B
Lymphocytes T
Lymphoma
Lymphoma, B-Cell - drug therapy
Lymphoma, B-Cell - immunology
Male
Middle Aged
Models, Biological
Monoclonal antibodies
Non-Hodgkin's lymphoma
Patients
Pharmacokinetics
Rituximab
Rituximab - administration & dosage
Rituximab - pharmacokinetics
Targeted cancer therapy
Young Adult
ISSN:1752-8054, 1752-8062, 1752-8062
Online-Zugang:Volltext
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Zusammenfassung:Mosunetuzumab (Mosun) is a CD20xCD3 T‐cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step‐up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B‐Cell Non‐Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05–2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step‐up dosing groups (0.4/1/2.8–1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti‐CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two‐compartment model with time‐dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady‐state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti‐CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti‐CD20 drug concentration (median = 10 μg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti‐CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation.
Bibliographie:Brendan Bender and Chi‐Chung Li co‐first authors.
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ISSN:1752-8054
1752-8062
1752-8062
DOI:10.1111/cts.13825