Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B‐Cell Hematological Malignancies

Abstract

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 (C trough ) 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. C trough 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.

Model‐Informed Drug Development: Connecting the Dots With a Totality of Evidence Mindset to Advance Therapeutics

“…Jamois et al present application of PK-clinical bridging to the model-informed development and approval of a fixed-dose subcutaneously administered formulation of the anti-CD20 antibody rituximab, for the treatment of hematologic malignancies. 16 Based on prior knowledge from clinical experience on intravenously administered rituximab that trough concentrations correlated with efficacy, and biological support based on an expectation that sustained saturation of Bcell CD20 receptors should be relevant for efficacy, the clinical development program was designed to underwrite the dosage for subcutaneous administration based on demonstration of noninferior trough concentrations. Phase III trials included PK noninferiority as their primary objective-a testament to the pivotal role played by quantitative clinical pharmacology in the development plan.…”

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology

“…Due to target-mediated drug disposition, elimination phase of the majority of these mAbs was described with dual clearance, linear at higher concentrations when saturation of the target is achieved, and non-linear at lower concentrations. The exceptions were rituximab, which has a time-dependent component due to B-cell depletion, 52,53 and pertuzumab, whose model did not enclose the non-linear component. 54 In the denosumab model, a quasi-steady-state approximation was used to characterize non-linear clearance.…”

“…Population pharmacokinetic (PK) parameters of monoclonal antibodies (mAbs) available as subcutaneous (SC) formulations[52][53][54][55][56][57][58] …”