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Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase.

ABSTRACT: Rituximab and trastuzumab were the first therapeutic monoclonal antibodies (mAbs) approved in oncology. Both antibodies are delivered by the intravenous (IV) route, but recently subcutaneous (SC) formulations have been developed. Subcutaneous administration of mAbs can offer substantial patient and resource benefits compared with IV, but SC administration of some mAbs can be limited by drug volume. Recombinant human hyaluronidase (rHuPH20) temporarily degrades hyaluronan, allowing SC delivery of drug volumes that might not otherwise be feasible.Clinical trials assessing coformulation of rituximab or trastuzumab with rHuPH20 for SC administration were reviewed.Phase I trials of rituximab SC maintenance therapy in patients with follicular lymphoma and trastuzumab SC in healthy volunteers and patients with early breast cancer have demonstrated substantially shorter administration times and comparable tolerability and pharmacokinetics compared with IV formulations. Rituximab SC 1400-mg and trastuzumab SC 600-mg doses were identified for further study. Phase III clinical data for rituximab SC 1400 mg have shown comparable efficacy to rituximab IV, and initial clinical data suggest comparable efficacy of trastuzumab SC 600 mg and the IV formulation.Coformulation with rHuPH20 may enable effective, well-tolerated, cost-effective, and convenient SC administration of rituximab and trastuzumab. Additional studies are ongoing.

SUBMITTER: Shpilberg O

PROVIDER: S-EPMC3776971 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase.

Shpilberg O O Jackisch C C

British journal of cancer 20130903 6

<h4>Background</h4>Rituximab and trastuzumab were the first therapeutic monoclonal antibodies (mAbs) approved in oncology. Both antibodies are delivered by the intravenous (IV) route, but recently subcutaneous (SC) formulations have been developed. Subcutaneous administration of mAbs can offer substantial patient and resource benefits compared with IV, but SC administration of some mAbs can be limited by drug volume. Recombinant human hyaluronidase (rHuPH20) temporarily degrades hyaluronan, allo ...[more]

PMID: 24002601

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Project description:Development of bio-therapeutics has exhibited exponential growth in China over the past decade. However, no biosimilar drug has been approved in China (CN) due to the lack of a national biosimilar regulatory guidance. HLX01, a rituximab biosimilar developed in China under European Medicines Agency biosimilar guidelines and requirements, was the first such drug submitted for regulatory review in China, and it is expected to receive approval there as a biosimilar product. To demonstrate the analytical similarities of HLX01, CN-rituximab (sourced in China but manufactured in Europe) and EU-rituximab (sourced and manufactured in Europe), an extensive 3-way physicochemical and functional similarity assessment using a series of orthogonal and state-of-the-art techniques was conducted, following the similarity requirement guidelines recently published by China's Center for Drug Evaluation. The results of the similarity study showed an identical protein amino acid sequence and highly similar primary structures between HLX01 and the reference product (RP) MabThera®, along with high similarities in higher order structures, potency, integrity, purity and impurity profiles, biological and immunological binding functions, as well as degradation behaviors under stress conditions. In addition, HLX01 presented slightly lower aggregates and better photostability compared with the RP. Despite slight changes in relative abundance of glycan moieties and heavy chain C-terminal lysine modification, no differences in biological activities and immunological properties were observed between the RP and HLX01. In conclusion, HLX01 is highly similar to CN- and EU-sourced RP in terms of physicochemical properties and biological activities, suggesting similar product quality, efﬁcacy, and safety. The regulatory requirements interpreted and applied towards the HLX01 marketing application sets a precedent for analytical similarity assessment of biosimilar products in China.

Project description:INTRODUCTION:Adjuvant trastuzumab is a standard of care in the treatment of Human Epidermal growth factor Receptor 2 (HER2) positive early breast cancer (eBC). Initially trastuzumab could only be administered intravenously (IV), however since 2013, a subcutaneous (SC) formulation with comparable efficacy and safety profile is available and preferred by patients. Trastuzumab SC does not require pharmacy preparation and has shorter administration time. The objective of this study was to estimate the economic efficiency of the SC formulation of trastuzumab by assessing the economic benefits of actual SC-driven process changes at one single Swedish healthcare institution. METHODS:This study analyzes changes in trastuzumab administration practice after the SC formulation was introduced at the Karolinska University Hospital. Process changes were identified and introduced in order to capitalize on the inherent work efficiency benefits of the SC formulation. Actual hospital data for 2015 were used to quantitatively estimate the annual economic impact of the changes. It encompassed administrative (i.e. non-medical) data of 178 newly diagnosed HER2-positive eBC patients and a total of 2,769 SC administrations. Realized economic benefits were expressed in hours saved by nurses, direct monetary cost savings and potential infusion fee revenue that could be earned through infrastructural revenue gains. RESULTS:In 2015, the replacement of IV infusion to SC administration generated total time savings of more than 1,100 hours, and led to direct monetary cost savings of 603,000 EUR. It unlocked a capacity gain of 1-2 additional administrations daily within the existing facility infrastructure. Given the current remuneration structure per administration, this revenue gain translated into an incremental revenue potential of up to 3 million EUR. CONCLUSION:Data from this study showed that the shift from trastuzumab IV to SC formulation resulted in significant economic effects in terms of departmental resources related to time, direct monetary cost savings, and infrastructural revenue gains.

Project description: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.

Dataset Information

Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase.

Publications

Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase.

Similar Datasets

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