Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial.

Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL.

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.

Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.

A subcutaneous formulation of the anti-CD20 antibody rituximab has been developed. Fixed-dose subcutaneous rituximab delivers noninferior serum trough concentrations (Ctrough ), ensuring similar target saturation and comparable efficacy/safety, to intravenous rituximab, but with simplified and shortened preparation and administration. We aimed to characterize the pharmacokinetic (PK) and exposure-response properties of subcutaneous rituximab. Data from two clinical trials were analyzed to describe PKs and pharmacodynamics in patients with chronic lymphocytic leukemia following intravenous and subcutaneous rituximab administration. Intravenous and subcutaneous rituximab were described by a linear two-compartment population PK model with time-dependent and time-independent clearances, and first-order subcutaneous absorption. Main covariates influencing exposure were body size and baseline white blood cell count. Occurrence of adverse events was not correlated with rituximab exposure. Although greater and more sustainable B-cell depletion was observed with higher exposure, inherent limitations to the data (use of one dose level, and time-dependent and target-impacted PKs) prevented reliable assessment of exposure-response relationships.