Non-Clinical Pharmacokinetic/Pharmacodynamic and Early Clinical Studies Supporting Development of a Novel Subcutaneous Formulation for the Monoclonal Antibody Rituximab
Open accessAbstract
This overview article describes the non-clinical pharmacology, pharmacokinetic and clinical dose-finding programs supporting the development of a novel subcutaneous formulation for rituximab, a monoclonal antibody that selectively targets CD20-positive B-lymphocytes. The subcutaneous route of administration is expected to improve convenience for patients and to reduce healthcare professional resource use compared with conventional intravenous infusion. Various non-clinical and clinical studies were conducted to support the bridge from the approved intravenous formulation to the novel subcutaneous treatment. The underlying hypothesis for these studies was that achieving subcutaneous rituximab serum trough concentrations that are at least as high as those reached with the intravenous formulation would result in at least the same degree of receptor saturation. Preclinical mouse xenograft and cynomolgus monkey B-cell depletion studies were performed at intravenous and subcutaneous doses that were previously found to result in comparable serum concentrations in pharmacokinetic studies in the same species. Results from these non-clinical assessments guided dose selection for the subsequent phase 1b dose finding trials in patients with follicular lymphoma as part of maintenance treatment. A fixed dose of 1 400 mg was found to result in noninferior serum trough concentrations to the intravenous formulation. Clinical trials in the induction setting in patients with follicular lymphoma and chronic lymphocytic leukemia are currently ongoing.
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Subcutaneous trastuzumab and rituximab are not approved for home- or self-administration and are dosed manually by a healthcare professional using a vial and handheld syringe in a hospital, physician's office, or infusion center.
“Subcutaneous trastuzumab and rituximab are not approved for home- or self-administration and are dosed manually by an HCP using a vial and handheld syringe in a hospital, physician’s office, or infusion center [32, 33].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [33]
While most monoclonal antibodies on the market for cancer treatment are administered intravenously, subcutaneous dosing alternatives have recently been developed, for example, trastuzumab for HER2-positive breast cancer and rituximab for non-Hodgkin's lymphoma.
“While most mAbs on the market for cancer treatment are administered intravenously, subcutaneous dosing alternatives have recently been developed, for example, trastuzumab (Herceptin) for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer and rituximab (MabThera/Rituxan Hycela) for non-Hodgkin’s lymphoma (NHL) [32, 33].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [33]
Contrasting with HyQvia, rHuPH20 is co-formulated with the subcutaneous active biotherapeutic, omitting the need for pre-injection of the enzyme.
“Contrasting with HyQvia, rHuPH20 is co-formulated with the subcutaneous active biotherapeutic, omitting the need for pre-injection of the enzyme (sequential administration) [32, 33].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [33]
The selection of a subcutaneous fixed dose for trastuzumab and rituximab was based on a pharmacokinetic bridging approach assuming that a subcutaneous dose achieving serum trough concentrations non-inferior to those with intravenous dosing would achieve comparable saturation of target receptors and result in noninferior efficacy.
“The selection of a subcutaneous fixed dose was based on a pharmacokinetic bridging approach assuming that a subcutaneous dose achieving serum trough concentrations (Ctrough) non-inferior to those with intravenous dosing would achieve comparable saturation of target receptors and result in noninferior efficacy [32, 33].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [33]
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References 12 · Cited by 32
Research works printed but not linked: 9
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- Review
- Bittner B et al. Development of Subcutaneous Rituximab … Drug Res 2014; 64: 569-575
- Ismael G , Hegg R , Muehlbauer S et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2- positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicenter, randomized trial . Lancet Oncol 2012 ; 13 : 869 -878
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- Authors
- Bittner, B., Richter, W., Hourcade-Potelleret, F., Herting, F., & Schmidt, J.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- F. Hoffmann-La Roche Ltd., Clinical Modeling & Simulation, Basel, Switzerland
- Roche Diagnostics GmbH, Penzberg, Germany
- Corresponding author
- Schmidt, J.
- Venue
- Drug Research
- Publisher
- Georg Thieme Verlag KG
- Published
- 2014-01-22
- Volume
- 64
- Issue
- 11
- Pages
- 569-575
- ISSN
- 2194-9379 (ISSN-L)
- 2194-9387
- OpenAlex
- W2019103756
- Cited by
- 32
- References
- 12
- Citations by year
- 2026: 4 · 2025: 1 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 1
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Drug Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- rituximab, subcutaneous formulation, monoclonal antibodies, CD20, pharmacokinetics, pharmacodynamics, dose-finding, B-cell depletion, follicular lymphoma, chronic lymphocytic leukemia, receptor saturation, non-inferiority
- MeSH terms
- Rituximab, Animals, Chemistry, Pharmaceutical, Clinical Trials as Topic, Humans, Injections, Subcutaneous, Mice, Antibodies, Monoclonal, Murine-Derived
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