An open-label clinical evaluation of tigecycline (TGC) concentrations in selected tissues and fluids

Abstract

Background/Aims TGC, an expanded spectrum glycylcycline in development for the treatment of skin and skin structure infections and intraabdominal infections, has a large volume of distribution (Vss≈600 L). TGC concentrations were measured in serum, lung, colon, gallbladder, bone, bile, and synovial fluid. Methods Serum TGC was determined (by LC/MS/MS) predose, at end of 30-minute infusion of the single 100-mg TGC dose, and at tissue collection (during scheduled elective surgery). Results At the time of this analysis, data from 54 subjects (of 120 planned) were available. Serum samples from 52 and tissue/fluid samples from 49 subjects were analyzed. Median TGC serum concentrations were 1425 ng/mL, 198 ng/mL, and 60 ng/mL at end of infusion, 4 hours, and 24 hours, respectively. Gallbladder, lung, and colon had the highest TGC concentrations; synovial fluid and bone had the lowest. One (1) death, the only serious adverse event (AE), occurred after the study; it was not related to TGC. Treatment-related AEs of nausea (23, 43%) and vomiting (7, 13%) were most frequently reported. No subject withdrew because of AEs. Conclusions Based on this analysis, a 100-mg TGC dose distributes into gallbladder, lung, and colon at or above MICs shown by in vitro data to be efficacious, and into bone tissue and synovial fluid. In animal studies, labeled TGC achieved high concentrations in bone. Tight TGC-bone binding, with poor extraction for assay, may have occurred in this study, rather than low bone uptake. The study is ongoing. (See Table). Clinical Pharmacology & Therapeutics (2005) 77, P98–P98; doi: 10.1016/j.clpt.2005.01.005 Table 1. Concentration Mean±SD tissue/serum ratios a 1 subject at each time point; NA=data not available; BQL=below quantitation limit. Range (ng/g) 4 hrs 8 hrs 12 hrs 24 hrs Gallbladder (n=17) 238–20,700 39±40 15±19 85±79 38±42 Lung (n=2) 653–1890 8.6a NA NA 14.6a Colon (n=11) 87–995 2.1±1.9 1.7±2.3 2.1±2.5 NA Bone (n=19) BQL-269 0.35±0.16 NA 1.10±1.25 NA Synovial fluid (n=15) 26–181 0.58±0.24 NA 0.89±0.49 0.71±0.15