Debio 1452 inhibits FabI, an essential enzyme in all staphylococci, resulting in specific, targeted spectrum of antibacterial activity. Debio 1450, the prodrug of Debio 1452 is being developed in IV and oral formulations for the treatment of complicated staphylococcal infections. The safety, tolerability and PK of IV administered Debio 1450 (the prodrug) and the active form Debio 1452, were evaluated in a Phase I study.
A double-blind, placebo-controlled, single dose escalation study in healthy volunteers. Eligible subjects were aged 18–55 y, male or female of non-childbearing potential. They were assigned to 6 planned dosing cohorts (48, 72, 108, 160, 240 and 320 mg of Debio 1450, each with 8 subjects (6 randomized to study drug, 2 to placebo). A single IV dose was administered over 2 h and blood samples taken at pre-defined points over 48 h for LC-MS/MS determination of plasma Debio 1450 and Debio 1452. Using a non-compartmental approach, single-dose PK parameters of Debio 1450 and Debio 1452 were derived from their plasma concentration versus time profiles. Safety and tolerability were assessed throughout.
Results: Demographic data were similar for both treatment groups; mean ages were 30.9–34.7 y, and 88% were male. The prodrug Debio 1450 peaked in plasma (Cmax) at 1–2 h after the start of infusion and was then rapidly converted into the active moiety Debio 1452, for which Cmax occurred within 30 min after the end of infusion. Debio 1452 then declined mono-exponentially with mean terminal half-lives of 7–8 h. Overall, plasma exposure of both Debio 1450 and Debio 1452 increased proportionally with the dose in the range of 48–320 mg. No deaths or SAEs were reported. No abnormalities in hematologic, biochemical, ECG, or urinalysis parameters were observed. Debio 1450 was well tolerated; adverse events were mild and included mainly headache.
- Plasma exposure to Debio 1450 and Debio 1452 was dose proportional
- Debio 1450 was rapidly converted to active Debio 1452, which exhibited long plasma elimination half-lives
- Debio 1450, administered as single IV doses (48–320 mg), was safe and well tolerated in healthy subjects
N. Kaplan, Debiopharm: Consultant , Consulting fee
V. N. Métral, Debiopharm: Employee , Salary
A. Ménétrey, Debiopharm: Employee , Salary
H. Alcorn Jr., None
F. Wittke, Debiopharm: Employee , Salary