ALAN J. FISCHMAN,1,2* JOHN W. BABICH,1 ALI A. BONAB,1 NATHANIEL M. ..... Barry, A. L., P. C. Fuchs, C. Thornsberry, J. C. McLaughlin, S. G. Jenkins,.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 1998, p. 2048–2054 0066-4804/98/$04.0010 Copyright © 1998, American Society for Microbiology. All Rights Reserved.
Vol. 42, No. 8
Pharmacokinetics of [18F]Trovafloxacin in Healthy Human Subjects Studied with Positron Emission Tomography ALAN J. FISCHMAN,1,2* JOHN W. BABICH,1 ALI A. BONAB,1 NATHANIEL M. ALPERT,1 JOHN VINCENT,3 RONALD J. CALLAHAN,1 JOHN A. CORREIA,1 1,2 AND ROBERT H. RUBIN Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, Boston,1 and Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology, Cambridge,2 Massachusetts, and Central Research Division, Pfizer Inc., Groton, Connecticut3 Received 14 November 1997/Returned for modification 20 March 1998/Accepted 30 April 1998
Tissue pharmacokinetics of trovafloxacin, a new broad-spectrum fluoroquinolone antimicrobial agent, were measured by positron emission tomography (PET) with [18F]trovafloxacin in 16 healthy volunteers (12 men and 4 women). Each subject received a single oral dose of trovafloxacin (200 mg) daily beginning 5 to 8 days before the PET measurements. Approximately 2 h after the final oral dose, the subject was positioned in the gantry of the PET camera, and 1 h later 10 to 20 mCi of [18F]trovafloxacin was infused intravenously over 1 to 2 min. Serial PET images and blood samples were collected for 6 to 8 h, starting at the initiation of the infusion. Drug concentrations were expressed as the percentage of injected dose per gram, and absolute concentrations were estimated by assuming complete absorption of the final oral dose. In most tissues, there was rapid accumulation of the radiolabeled drug, with high levels achieved within 10 min after tracer infusion. Peak concentrations of more than five times the MIC at which 90% of the isolates are inhibited (MIC90) for most members of Enterobacteriaceae and anaerobes (>10-fold for most organisms) were achieved in virtually all tissues, and the concentrations remained above this level for more than 6 to 8 h. Particularly high peak concentrations (micrograms per gram; mean 6 standard error of the mean [SEM]) were achieved in the liver (35.06 6 5.89), pancreas (32.36 6 20.18), kidney (27.20 6 10.68), lung (22.51 6 7.11), and spleen (21.77 6 11.33). Plateau concentrations (measured at 2 to 8 h; micrograms per gram; mean 6 SEM) were 3.25 6 0.43 in the myocardium, 7.23 6 0.95 in the lung, 11.29 6 0.75 in the liver, 9.50 6 2.72 in the pancreas, 4.74 6 0.54 in the spleen, 1.32 6 0.09 in the bowel, 4.42 6 0.32 in the kidney, 1.51 6 0.15 in the bone, 2.46 6 0.17 in the muscle, 4.94 6 1.17 in the prostate, and 3.27 6 0.49 in the uterus. In the brain, the concentrations (peak, ;2.63 6 1.49 mg/g; plateau, ;0.91 6 0.15 mg/g) exceeded the MIC90s for such common causes of central nervous system infections as Streptococcus pneumoniae (MIC90,
