title: A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components.
abstract: Subcutaneous (SC) injection is becoming a more common route for the administration of biopharmaceuticals. Currently, there is no reliable in vitro method that can be used to anticipate the in vivo performance of a biopharmaceutical formulation intended for SC injection. Nor is there an animal model that can predict in vivo outcomes such as bioavailability in humans. We address this unmet need by the development of a novel in vitro system, termed Scissor (Subcutaneous Injection Site Simulator). The system models environmental changes that a biopharmaceutical could experience as it transitions from conditions of a drug product formulation to the homeostatic state of the hypodermis following SC injection. Scissor uses a dialysis-based injection chamber, which can incorporate various concentrations and combinations of acellular extracellular matrix (ECM) components that may affect the release of a biopharmaceutical from the SC injection site. This chamber is immersed in a container of a bicarbonate-based physiological buffer that mimics the SC injection site and the infinite sink of the body. Such an arrangement allows for real-time monitoring of the biopharmaceutical within the injection chamber, and can be used to characterize physicochemical changes of the drug and its interactions with ECM components. Movement of a biopharmaceutical from the injection chamber to the infinite sink compartment simulates the drug migration from the injection site and uptake by the blood and/or lymph capillaries. Here, we present an initial evaluation of the Scissor system using the ECM element hyaluronic acid and test formulations of insulin and four different monoclonal antibodies. Our findings suggest that Scissor can provide a tractable method to examine the potential fate of a biopharmaceutical formulation after its SC injection in humans and that this approach may provide a reliable and representative alternative to animal testing for the initial screening of SC formulations.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address: hanne.kinnunen@durham.ac.uk.
authors.forename: Hanne M
authors.initials: HM
authors.lastname: Kinnunen
authors.affiliation: Late Stage Pharmaceutical Development, Genentech, Inc. South San Francisco, CA 94080, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Luis Rodrigo
authors.initials: LR
authors.lastname: Contreras-Rojas
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Chlöe
authors.initials: C
authors.lastname: Alleman
authors.affiliation: Late Stage Pharmaceutical Development, Genentech, Inc. South San Francisco, CA 94080, USA.
authors.forename: Alavattam
authors.initials: A
authors.lastname: Sreedhara
authors.affiliation: Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU F. Hoffmann-La Roche Ltd, Basel CH-4070, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Pharmacokinetics, Genentech, Inc. South San Francisco, CA 94080, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Khawli
authors.affiliation: Drug Delivery, Genentech, Inc. South San Francisco, CA 94080, USA.
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Yohe
authors.affiliation: Pharmacokinetics, Genentech, Inc. South San Francisco, CA 94080, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.affiliation: Late Stage Pharmaceutical Development, Genentech, Inc. South San Francisco, CA 94080, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Patapoff
authors.affiliation: Drug Delivery, Genentech, Inc. South San Francisco, CA 94080, USA.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Daugherty
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address: Rjm37@bath.ac.uk.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Mrsny
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001639:Bicarbonates / Q000737:chemistry; D001688:Biological Products / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002021:Buffers; D002626:Chemistry, Pharmaceutical; D003956:Dialysis; D015195:Drug Design; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007279:Injections, Subcutaneous; D008196:Lymph / Q000378:metabolism; D040521:Subcutaneous Tissue / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D001639:Bicarbonates; D001688:Biological Products; D002021:Buffers; D006820:Hyaluronic Acid
keywords: Biopharmaceuticals; Formulation design; In vitro model; Subcutaneous injection