Author(s): Miltenburg AM, Prohn M, van Kuijk JH, Tiessen RG, de Kort M,
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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 CarboCarrierÂ® insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrierÂ® insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrierÂ® insulin in healthy volunteers were explored, and the dose-response relationship and relative bioactivity of CarboCarrierÂ® 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 CarboCarrierÂ® insulin were compared with those of NPH-insulin. RESULTS: CarboCarrierÂ® insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrierÂ® insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28 h. All CarboCarrierÂ® insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group. CONCLUSIONS: CarboCarrierÂ® 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 CarboCarrierÂ® technology by making use of CarboCarrierÂ® insulin as an example. Â© 2012 MSD Oss B.V., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. British Journal of Clinical Pharmacology Â© 2012 The British Pharmacological Society.
This article was published in Br J Clin Pharmacol
and referenced in Intellectual Property Rights: Open Access