Decreased Subcutaneous Bioavailability of an Oxyntomodulin Analog in a Controlled Release Formulation could be Caused by Skin Metabolism in Rats

Abstract

Objectives In vivo and in vitro studies were conducted to understand the potential cause for the reduced bioavailability of Peptide A, an Oxyntomodulin analog, following subcutaneous administration in the controlled release formulation compared to that in the instant release formulation, in spite of a prolonged half-life achieved by the controlled release formulation. Methods Concentrations in plasma, urine, feces and/or a panel of tissues including skin were measured after intravenous or subcutaneous administration of Peptide A or [I125] Peptide A to rats. Dose recovery, pharmacokinetic parameters and skin absorption kinetics were estimated. In vitro skin stability in rats was also performed for [I125] Peptide A. HPLC radio chromatography was used to elucidate peptide degradation in skin from in vivo and in vitro studies. Results The near complete recovery of total radioactivity after subcutaneous administration of [125I] Peptide A excluded the possibility that the reduced exposure was due to incomplete absorption. A major degradant peak of Peptide A from HPLC radio chromatography was observed in skin samples collected from the injection site after subcutaneous administration or from in vitro skin stability study. Conclusions An in vitro study was developed to be able to test stability of the peptide in skin. The results fromboth in vivo and in vitro studies suggested that degradation of Peptide A in skin during its prolonged residence at theinjection site after subcutaneous administration in the controlled release formulation could potentially contribute toa decrease in subcutaneous bioavailability despite of an increased half-life. Thus, caution needs to be taken whilechoosing the right strategy to extend half-life.An in vitro study was developed to be able to test stability of the peptide in skin. The results from both in vivo and in vitro studies suggested that degradation of Peptide A in skin during its prolonged residence at the injection site after subcutaneous administration in the controlled release formulation could potentially contribute to a decrease in subcutaneous bioavailability despite of an increased half-life. Thus, caution needs to be taken while choosing the right strategy to extend half-life.