603. Pharmacokinetics, Safety and Tolerability of a Novel Fluorocycline, TP-434, Following Multiple Dose Oral Administration With and Without Food
Session: Poster Abstract Session: Novel Antimicrobial Agents
Friday, October 21, 2011
Room: Poster Hall B1
Background: TP-434 is a novel broad-spectrum fluorocycline antibiotic with potent activity and efficacy against multidrug-resistant (MDR) gram-negative and gram-positive aerobic and anaerobic pathogens, including Enterobacteriaceae expressing extended-spectrum beta-lactamases and/or carbapenemases, MRSA, and VRE; it has limited activity against Pseudomonas spp. TP-434 is currently being evaluated intravenously (IV) in a phase 2 study for the treatment of community-acquired complicated intra-abdominal infections.  The current phase 1 study investigated the safety, tolerability and pharmacokinetic (PK) profile of TP-434 when administered orally after multiple daily doses.

Methods: Unformulated TP-434 was administered orally as single daily doses of 50, 100, 200 and 300 mg in a gelatin capsule for 7 days.  Routine safety assessments and blood samples for PK analyses were obtained.  The 100 mg dose was also administered as a single dose in both the fasting and fed states to determine the effect of food on the PK parameters.

Results: AUC and Cmax are listed below; T1/2 was 14-21 hours on Day 1 and 17-36 hours on Day 7

Dose (mg)

Day 1

Day7

Cmax (ng/mL)

AUC (ng*hr/mL)

Cmax (ng/mL)

AUC(ng*hr/mL)

100

fast (n=8)

117

1924

 

 

fed (n=8)

41

724

 

 

light (n=6)

43

496

48

902

300

fast (n=6)

206

3154

342

9511

light = light breakfast, fed = FDA specified breakfast, fast = minimum 8 hour fast

Safety results remain blinded, with 2 placebo subjects in each group.  No SAEs were reported.  No significant safety signals were observed.   No nausea was reported in the 50-200 mg dose groups.  Three subjects in the 300 mg group reported nausea, 2 of whom had at least 1 episode of emesis – all mild and transient.  No subject discontinued treatment.

Conclusion: 

  • TP-434 is orally bioavailable, indicating the potential for IV/oral step-down therapy, or oral therapy alone
  • There is a significant effect of food on the oral absorption of TP-434
  • No significant safety signals were observed
  • TP-434 is tolerated at doses producing what is expected to be therapeutic levels

Subject Category: A. Antimicrobial agents and Resistance

Patrick T Horn, MD, PhD1, Joyce A Sutcliffe, PhD1, Susannah Walpole, PhD1 and Anton Leighton, MD2, (1)Tetraphase Pharmaceuticals, Watertown, MA, (2)Medical Consultant, Oakland, CA

Disclosures:

P. T. Horn, Tetraphase Pharmaceuticals: Employee, Salary

J. A. Sutcliffe, Tetraphase Pharmaceuticals: Employee, Salary

S. Walpole, Tetraphase Pharmaceuticals: Employee, Salary

A. Leighton, Tetraphase Pharmaceuticals: Consultant, Salary

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.