title: Pharmacokinetics, biocompatibility and bioavailability of a controlled release monoclonal antibody formulation.
abstract: The sustained and localized delivery of monoclonal antibodies has become highly relevant, because of the increasing number of investigated local delivery applications in recent years. As the local delivery of antibodies is associated with high technological hurdles, very few successful approaches have been reported in the literature so far. Alginate-based delivery systems were previously described as promising sustained release formulations for monoclonal antibodies (mAbs). In order to further investigate their applicability, a single-dose animal study was conducted to compare the biocompatibility, the pharmacokinetics and the bioavailability of a human monoclonal antibody liquid formulation with two alginate-based sustained delivery systems after subcutaneous administration in rats. 28 days after injection, the depot systems were still found in the subcutis of the animals. A calcium cross-linked alginate formulation, which was injected as a hydrogel, was present as multiple compartments separated by subcutaneous tissue. An in situ forming alginate formulation was recovered as a single compact and cohesive structure. It can be assumed that the multiple compartments of the hydrogel formulation led to almost identical pharmacokinetic profiles for all tested animals, whereas the compact nature of the in situ forming system resulted in large interindividual variations in pharmacokinetics. As compared to the liquid formulation the hydrogel formulations led to lower mAb serum levels, and the in situ forming system to a shift in the time to reach the maximum mAb serum concentration (Tmax) from 2 to 4 days. Importantly, it was shown that after 28 days only marginal amounts of residual mAb were present in the alginate matrix and in the tissue at the injection site indicating nearly complete release. In line with this finding, systemic drug bioavailability was not affected by using the controlled release systems. This study successfully demonstrates the suitability and underlines the potential of polyanionic systems for local and controlled mAb delivery.
authors.affiliation: Novartis Pharma AG, Biologics Process Research & Development, 4002 Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schweizer
authors.forename: Igor
authors.initials: I
authors.lastname: Vostiar
authors.forename: Annabelle
authors.initials: A
authors.lastname: Heier
authors.forename: Tim
authors.initials: T
authors.lastname: Serno
authors.forename: Karin
authors.initials: K
authors.lastname: Schoenhammer
authors.forename: Michael
authors.initials: M
authors.lastname: Jahn
authors.forename: Stewart
authors.initials: S
authors.lastname: Jones
authors.forename: Aline
authors.initials: A
authors.lastname: Piequet
authors.forename: Christian
authors.initials: C
authors.lastname: Beerli
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.forename: Achim
authors.initials: A
authors.lastname: Goepferich
mesh_terms: D000464:Alginates / Q000737:chemistry*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D003692:Delayed-Action Preparations / Q000737:chemistry*; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000032:analysis; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000464:Alginates; D000911:Antibodies, Monoclonal; D003692:Delayed-Action Preparations; D006603:Hexuronic Acids; D007074:Immunoglobulin G; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D020723:Glucuronic Acid
keywords: Alginate; Antibody; Bioavailability; Biocompatibility; Controlled release; Pharmacokinetics