Sitafloxacin Hydrate

Sitafloxacin is one of the oral respiratory quinolones for the treatment of community‐acquired pneumonia. The pharmacokinetic (PK) changes of sitafloxacin in critical illness have been previously reported. However, sitafloxacin exposure and target attainment have never been confirmed in this population. To develop a population pharmacokinetic (PK) model of sitafloxacin, plasma and epithelial lining fluid (ELF) concentrations were obtained after sitafloxacin administration as a 200‐mg single dose under fasting condition in 12 subjects. A population pharmacokinetic analysis was performed using a nonlinear mixed‐effects modeling approach. The probability of target attainment (PTA) and cumulative fraction of response (CFR) against the MIC distribution of S. pneumoniae isolated from Thai patients was estimated by Monte Carlo simulations. The pharmacokinetics of sitafloxacin in plasma was best described by a one‐compartment model linking to the ELF compartment. The partition coefficient which relates drug exposure in ELF to drug exposure in plasma was estimated to be 0.77. Age was a significant covariate that impacted the relative bioavailability. Results from Monte Carlo simulations showed that the maximum approved dose of sitafloxacin 100 mg q 12 h provided > 90% PTA and CFR in both plasma and ELF. The current maximal dosing of sitafloxacin provided adequate exposure in plasma and ELF for the treatment of critically ill Thai patients with pneumonia.

The purpose of this study was to investigate the correlation between the dissolution profiles of salt-form drugs in biorelevant bicarbonate buffer and oral drug absorption.

Ciprofloxacin HCl (CPFX HCl), garenoxacin mesylate (GRNX MS), tosufloxacin tosylate (TFLX TS), levofloxacin free-form (LVFX FF), and sitafloxacin free-form (STFX FF) were employed as model drugs. Bicarbonate buffer fasted state simulated intestinal fluid (BCB-FaSSIF) was used as a biorelevant dissolution medium (pH 6.5, BCB 10 mM (floating lid method), taurocholic acid (3 mM) and lecithin (0.75 mM)). The fraction of a dose absorbed in humans (Fa) was predicted by a simple theoretical framework for oral drug absorption using equilibrium solubility at pH 6.5 (Seq,pH6.5) or average dissolved drug concentration in the dissolution tests (Cdissolv,AV).

Fa was adequately predicted using Seq,pH6.5 for LVFX FF and STFX FF, however, underpredicted for CPFX HCl (tenfold), GRNX MS (twofold), and TFLX TS (sevenfold). When compendial Dose/FV was used for the dissolution test of CPFX HCl, bulk pH (pHbulk) remained unchanged and Cdissolv,AV ≈ Seq,pH6.5, resulting in a tenfold underprediction of Fa. Using clinical Dose/FV, pHbulk was decreased, Cdissolv,AV was increased, resulting in adequate Fa prediction. Similarly, for GRNX MS and TFLX TS, Fa predictability was improved using Cdissolv,AV at clinical Dose/FV. In these conditions, Cdissolv,AV > Seq,pH6.5 due to decreased pHbulk below the first pKa of the drugs.

The use of clinical Dose/FV was important for improving the correlation between the biorelevant dissolution profiles and Fa for salt-form drugs.