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.
Highlights
The CD20-specific monoclonal antibody rituximab (MabThera®, Rituxan®) was the first mAb approved for use in the treatment of cancer
Rituximab is widely used as the backbone of treatment for patients with non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) [1,2]
A novel SC formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme is under investigation to overcome the dose volume limitation. rHuPH20 functions as a permeation-enhancing agent that temporarily depolymerizes the local interstitial matrix component hyaluronan at the SC injection site and thereby increases the dispersion, absorption, and bioavailability of larger volumes of co-injected drugs [12,13]. It is important for rituximab SC administration to result in effective dissemination from the injection site in order to achieve adequate serum concentrations for rituximab distribution to lymphoid tissues throughout the body, as this is critical for the efficacy of rituximab in targeting malignant B cells for depletion [14]. In these preclinical studies we evaluated the pharmacokinetics (PK) of a single dose (20 mg/kg) of rituximab SC and compared the PK, pharmacodynamics (PD) of CD20 target coverage, and B-cell depletion efficacy associated with two 10 mg/kg doses, given 7 days apart, for rituximab IV versus rituximab SC in cynomolgus monkeys, a widely used model to study therapies aimed at Bcell depletion [15,16]
Summary
The CD20-specific monoclonal antibody (mAb) rituximab (MabThera®, Rituxan®) was the first mAb approved for use in the treatment of cancer. Rituximab is widely used as the backbone of treatment for patients with non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) [1,2]. Rituximab is currently administered by intravenous (IV) infusion at a dose of 375 mg/m2 (NHL) or 500 mg/m2 (CLL) body surface area [3]. The initial rate for first infusions of rituximab is 50 mg/h and, in the absence of infusion-related reactions, this can be increased by 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h. Subsequent doses of rituximab can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h increments at 30-minute intervals, to a maximum of 400 mg/h [3]. Typical total infusion times average 6 hours for the first infusion and 4 hours for subsequent infusions
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