Pharmacokinetics of [ ¹⁸ F]Trovafloxacin in Healthy Human Subjects Studied with Positron Emission Tomography

Abstract

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 ofEnterobacteriaceae 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 ± standard error of the mean [SEM]) were achieved in the liver (35.06 ± 5.89), pancreas (32.36 ± 20.18), kidney (27.20 ± 10.68), lung (22.51 ± 7.11), and spleen (21.77 ± 11.33). Plateau concentrations (measured at 2 to 8 h; micrograms per gram; mean ± SEM) were 3.25 ± 0.43 in the myocardium, 7.23 ± 0.95 in the lung, 11.29 ± 0.75 in the liver, 9.50 ± 2.72 in the pancreas, 4.74 ± 0.54 in the spleen, 1.32 ± 0.09 in the bowel, 4.42 ± 0.32 in the kidney, 1.51 ± 0.15 in the bone, 2.46 ± 0.17 in the muscle, 4.94 ± 1.17 in the prostate, and 3.27 ± 0.49 in the uterus. In the brain, the concentrations (peak, ∼2.63 ± 1.49 μg/g; plateau, ∼0.91 ± 0.15 μg/g) exceeded the MIC90s for such common causes of central nervous system infections asStreptococcus pneumoniae (MIC90, <0.2 μg/ml), Neisseria meningitidis (MIC90, <0.008 μg/ml), and Haemophilus influenzae(MIC90, <0.03 μg/ml). These PET results suggest that trovafloxacin will be useful in the treatment of a broad range of infections at diverse anatomic sites.

Liver tissue concentrations of levofloxacin after single intravenous administration of 500mg for antibiotic prophylaxis in liver surgery

“…In agreement with previous reports on other fluoroquinolones such as trovafloxacin [12] or fleroxacin [13], the liver tissue concentrations in our patients were higher than in other tissues [2,7,14], indicating exceptionally good penetration of levofloxacin into the liver. An abstract describing levofloxacin concentrations in liver tissue after repeated administration showed higher concentrations than in our study, which might be due to various factors such as tissue sampling several days after transarterial catheter embolization in hepatocellular carcinoma with repeated administration and a different, namely Japanese, study population [15].…”

Hotspot Dosages of Most Rapid Antibiotic Resistance Evolution

“…However, the large, 256-fold increase in MIC to erythromycin seen in the patient is not one we observe, indicating that other factors, such as cross-resistance resulting from multidrug therapy may play a role in hastening resistance in the clinic relative to this lab study. Antibiotic gradients within tissues 20 is another possible feature of in vivo treatments that is absent from our model which could increase selection for resistance.…”

Pet Imaging of the Pharmacokinetics of Small Molecular‐weight Drugs

“…The tissue PK of this drug was evaluated by PET imaging of [ 18 F]trovofloxacin [15]. The tissue PK of this drug was evaluated by PET imaging of [ 18 F]trovofloxacin [15].…”