Half-life prolongation of therapeutic proteins by conjugation to ATIII-binding pentasaccharides: a first-in-human study of CarboCarrier® insulin.
Br J Clin Pharmacol
; 75(5): 1221-30, 2013 May.
Article
em En
| MEDLINE
| ID: mdl-22978318
ABSTRACT
AIM:
Conjugation to antithrombin III ATIII-binding pentasaccharides has been proposed as a novel method to extend the half-life of therapeutic proteins. We aim to validate this technological concept in man by performing a first-in-human study using CarboCarrier® insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier® insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier® insulin in healthy volunteers were explored, and the dose-response relationship and relative bioactivity of CarboCarrier® insulin in subjects with type 2 diabetes were investigated.METHODS:
After an overnight fast, subjects were randomized to a treatment sequence. PK and pharmacodynamic (glucose, insulin and C-peptide) samples were obtained for up to 72 h post-dose. Effects of CarboCarrier® insulin were compared with those of NPH-insulin.RESULTS:
CarboCarrier® insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier® insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28 h. All CarboCarrier® insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group.CONCLUSIONS:
CarboCarrier® insulin is pharmacologically active showing features of insulin action in man. The elimination half-life of the molecule was clearly extended compared with endogenous insulin, indicating that conjugation to ATIII-binding pentasaccharides is a viable approach to extend the half-life of therapeutic proteins in humans. This is an important step towards validation of the CarboCarrier® technology by making use of CarboCarrier® insulin as an example.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Portadores de Fármacos
/
Glicoproteínas
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Insulina de Ação Prolongada
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Diabetes Mellitus Tipo 2
/
Hipoglicemiantes
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Adolescent
/
Adult
/
Aged
/
Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Holanda