PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Autor: Claire T. Sayers, David M. Haddleton, David J. Brayden, Xuexuan Wang, Jesus M. Frias, Sinéad M. Ryan
Přispěvatelé: Science Foundation Ireland Strategic Research Cluster Grant 07/SRC/B1154
Rok vydání: 2010
Předmět:
Male
Polymers
Chemical and Pharmacologic Phenomena
Pharmaceutical Science
Polyethylene Glycols
Substrate Specificity
Drug Stability
Cyclic AMP
Osteoporosis--drug therapy
Chromatography
High Pressure Liquid
Drug Carriers
Chymotrypsin
biology
Bone Density Conservation Agents
Chemistry
PEGylation
Trypsin
Bioconjugates
Intestines
Biochemistry
Liver
Amino Acids
Peptides
and Proteins
Methacrylates
conjugated peptides
Injections
Intraperitoneal
medicine.drug
Calcitonin
Pharmaceutics and Drug Design
Models
Biological
salmon calcitonin
Pharmacokinetics
Polymethacrylic Acids
In vivo
Cell Line
Tumor
PEG ratio
medicine
Potency
Animals
Humans
Rats
Wistar
Pharmacokinetic modelling
Chromatography
Binding Sites
comb-shaped polymers
Pharmacy and Pharmaceutical Sciences
osteoporosis
Rats
Molecular Weight
Conjugated peptides
biology.protein
pharmacokinetic modelling
Calcium
Peptides
Conjugate
Zdroj: Articles
ISSN: 1873-4995
Popis: Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel comb-shaped end-functionalised (poly(PEG) methyl ether methacrylate) (sCT-P) polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E max and an EC 50 of 3.7 nM. In vivo , while free sCT and the conjugates reduced serum [calcium] to a maximum of 15–30% over 240 min, the half-life (T 1/2 ) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40 kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T 1/2 for sCT, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.
Databáze: OpenAIRE
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