Safety, tolerability, pharmacokinetics and pharmacodynamics of parenterally administered dutogliptin: A prospective dose-escalating trial.

Aims: Animal studies suggest that inhibition of dipeptidyl peptidase 4 (DPP-IV) may improve heart function and survival after myocardial infarction by increasing cardiac myocytes' regenerative capacity. Parenterally administered dutogliptin may provide continuous strong DPP-IV inhibition to translate these results into humans. This trial investigated the safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of parenterally administered dutogliptin after single and repeated doses.

Methods: In an open-label trial, volunteers received dutogliptin at increasing doses of 30-120 mg subcutaneously or 30 mg intravenously in the single-dose cohorts. Subjects in the multiple-dose cohort received 60, 90 or 120 mg dutogliptin subcutaneously once daily on 7 consecutive days.

Results: Forty healthy males were included in the trial. No related serious adverse events occurred. Mild local injection site reactions with no requirement for intervention comprised 147 of 153 (96%) related adverse events. Subcutaneous bioavailability was approximately 100%. Multiple injections at daily intervals did not lead to the accumulation of the study drug. The accumulation ratios based on AUC range from 0.90 to 1.03, supporting this argument. All subjects receiving ≥60 mg dutogliptin yielded a maximum DPP-IV inhibition >90%. The duration of DPP-IV inhibition over time increased in a dose-dependent manner and was highest in the 120-mg multiple-dosing cohort with a maximum AUEC of 342 h % (standard deviation: 73), translating into 86% DPP-IV inhibition 24 hours after dosing.

Conclusion: Parenteral injection of dutogliptin was safe and subcutaneous bioavailability is excellent. DPP-IV inhibition increased dose dependently to >86% over 24 hours after multiple doses of 120 mg dutogliptin.