Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B‐Cell Hematological Malignancies
| Autor: | Artem Zharkov, Axel Boehnke, Christine McIntyre, Peter N. Morcos, Linda Lundberg, Ekaterina Gibiansky, Martin Barrett, Clarisse Chavanne, Nicolas Frey, Candice Jamois, Leonid Gibiansky |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Male medicine.medical_specialty Chronic lymphocytic leukemia Injections Subcutaneous Population Follicular lymphoma 030226 pharmacology & pharmacy Article law.invention 03 medical and health sciences Route of administration 0302 clinical medicine Antineoplastic Agents Immunological Pharmacokinetics law immune system diseases Internal medicine hemic and lymphatic diseases medicine Humans Pharmacology (medical) Dosing education Pharmacology education.field_of_study Clinical pharmacology Dose-Response Relationship Drug business.industry Research Articles medicine.disease Leukemia Lymphocytic Chronic B-Cell 030220 oncology & carcinogenesis Pharmacology Clinical Rituximab Administration Intravenous Female Lymphoma Large B-Cell Diffuse business medicine.drug |
| Zdroj: | Clinical Pharmacology and Therapeutics |
| ISSN: | 1532-6535 0009-9236 |
| Popis: | A fixed-dose subcutaneous (s.c.) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating to intravenous (i.v.) dosing, and has been approved based upon a pharmacokinetic (PK)-clinical bridging strategy, which demonstrated noninferiority of s.c. vs. i.v. dosing in malignancies, including follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). A clinical development plan was undertaken to identify rituximab s.c. doses achieving noninferior exposure to rituximab i.v., and to confirm PK-clinical bridging, with the same efficacy and similar safety. This drew upon data from 1,579 patients with FL, CLL, or diffuse large B-cell lymphoma in 5 clinical studies, and showed minimum steady-state serum concentration (Ctrough ) as the most appropriate exposure bridging measure. Population PK models were developed, simulations were run using covariates and PK parameters from clinical studies, and exposure-efficacy and -safety analyses performed. Population PKs showed a two-compartment model with time-dependent and -independent clearances. Clearance and volume were predominantly influenced by body surface area; disposition and elimination were similar for the s.c. and i.v. formulations. After s.c. administration, patients with FL and CLL achieved noninferior exposures to i.v. dosing. Overall, rituximab exposure and route of administration did not influence clinical responses in patients with FL or CLL, and there was no association between exposure and safety events. Ctrough was shown to be an effective pharmacologic-clinical bridging parameter for rituximab in patients with FL or CLL. Clinically effective exposures are achieved with either s.c. or i.v. dosing. |
| Databáze: | OpenAIRE |
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