Subcutaneous versus Intravenous Administration of Rituximab: Pharmacokinetics, CD20 Target Coverage and B-Cell Depletion in Cynomolgus Monkeys

Abstract

The CD20-specific monoclonal antibody rituximab (MabThera®, Rituxan®) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4–6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite initial peak serum drug level differences, subcutaneous rituximab has similar durability, pharmacodynamics, and efficacy compared with intravenous rituximab.

Subcutaneous Veltuzumab, a Humanized Anti-CD20 Antibody, in the Treatment of Refractory Pemphigus Vulgaris

“…Cynomolgus monkeys receiving low-dose subcutaneous veltuzumab demonstrated complete depletion of B cells in the peripheral blood, spleen, and mandibular and mesenteric lymph nodes, whereas rituximab effectively depleted B cells in the peripheral blood, but not consistently in the lymph nodes and/or spleen. 12,13 Consistent with this enhanced anti–B-cell activity, low-dose subcutaneous veltuzumab has shown efficacy comparable to that of intravenous rituximab in phase 1 studies of patients with non-Hodgkin lymphoma 6 and relapsed immune thrombocytopenia (ITP). 7 …”

Evaluating the benefits of transitioning from intravenous to subcutaneous Rituximab for Alberta cancer patients

“…There is no associated cost related to health care provider (nursing) preparation time with the administration of subcutaneous Rituximab, as a nurse does not use preparation time. For the purpose of this analysis, independent double-checking *C-trough refers to the minimum serum drug concentration during a given dosing interval (Mao et al, 2013). **AUC is the area under the curve in a plot concentration of drug in blood plasma against time (Mao et al, 2013).…”

“…THE NOVEL APPROACH R ituximab is a monoclonal antibody that targets the CD20+ B cell and is commonly used to treat hematologic disorders such as Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin's Lymphoma (NHL) (Mao, Brovarney, Dabbagh, Birnbock, Richter, & Del Nagro, 2013). In Alberta, Rituximab is approved to be administered via intravenous route only (Alberta Health Services (AHS, 2013).…”

“…In Alberta, Rituximab is approved to be administered via intravenous route only (Alberta Health Services (AHS, 2013). It is well documented there is greater potential for a risk of hypersensitivity associated with the use of this drug intravenously (Mao et al, 2013). Due to the risk of hypersensitivity, prophylactic medications are administered prior to chemotherapy (Biogen Idec and Genentech, 2006).…”

Non-Clinical Pharmacokinetic/Pharmacodynamic and Early Clinical Studies Supporting Development of a Novel Subcutaneous Formulation for the Monoclonal Antibody Rituximab

“…A further study was conducted to support planning and SC dose selection for a pharmacology study on B-cell depletion in cynomolgus monkeys (see non-clinical pharmacology studies section). In this study, male cynomolgus monkeys were administered a single dose of rituximab SC at 20 mg/kg [ 17 ] . The…”