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

Abstract

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 0-24h 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 0-24h 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.

Regulation and Dysregulation of Endothelial Permeability during Systemic Inflammation

“…However, intravenous administration of sitagliptin was well tolerated in healthy volunteers, protects the vasculature and has cardio- and reno-protective effects [ 188 , 189 , 190 ]. Additionally, a novel formulation for intravenous DPP4 inhibition is currently under consideration [ 191 ], smoothing the way for the transfer from bench to bedside. Accordingly, DPP4 inhibition during systemic inflammation may protect the vascular barrier function by controlling procalcitonin effects and may thus merit clinical evaluation in patients with systemic inflammation.…”

“Protocol for a phase 2, randomized, double-blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-myocardial infarction”: study protocol for a randomized controlled trial

“…In a phase 1 study [20] in healthy volunteers, dutogliptin was administered subcutaneously at doses ranging from 30 to 120 mg/day. Inhibition of plasma DPP4 increased in duration with increasing dose.…”

A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections

“…Regarding the ideal timing of sitagliptin administration, in preclinical animal (mouse) studies, ideal intravenous administration of sitagliptin 6 h after the onset of polymicrobial sepsis disease promises outstanding results [ 217 , 221 ]. Currently, glyptins are only approved for oral administration, but because of the gastroparesis and alterations in oral bioavailability that occur in septic patients, studies have been conducted in healthy volunteers on intravenous administration of sitagliptin, which was well tolerated and showed protective effects on the vessels, heart, and kidneys [ 6 , 9 , 12 , 215 , 231 , 232 , 233 , 234 , 235 , 236 ].…”