ABSTRACT
Gemifloxacin mesylate (GFM) is a synthetic, broad-spectrum, fluoroquinolone antibacterial agent. It is different from other class members because it achieves adequate plasma concentrations to inhibit both topoisomerase IV and gyrase. The aim of this study was to develop and validate a dissolution test for GFM in coated tablets, using a simulated absorption profile based on in vivo data obtained from the literature. The fraction and percentage of the dose absorbed were calculated using model-dependent Loo-Riegelman approach for two compartments. The best in vitro dissolution profile was obtained using 900 mL of pH 6.0 phosphate buffer as a dissolution medium at 37 °C ± 0.5 °C and paddles at 50 rpm. The in vitro dissolution samples were analyzed using a liquid chromatography method, and the validation was performed according to USP 34 (2011). The method showed specificity, precision, accuracy, robustness and linearity. Under these conditions, a level-A in vitro-in vivo correlation was suggested (r = 0.9926). The prediction errors were calculated to determine the validity and accuracy of the suggested correlation. The dissolution test can be used to evaluate the dissolution profile of GFM-coated tablets and minimize the number of bioavailability studies as part of new formulation development.
Subject(s)
Anti-Bacterial Agents/chemistry , Drug Industry/methods , Fluoroquinolones/chemistry , Intestinal Absorption , Models, Biological , Naphthyridines/chemistry , Topoisomerase Inhibitors/chemistry , Animals , Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/pharmacokinetics , Biological Availability , Brazil , Chromatography, High Pressure Liquid , Computer Simulation , Drug Industry/instrumentation , Drug Liberation , Fluoroquinolones/analysis , Fluoroquinolones/blood , Fluoroquinolones/pharmacokinetics , Gemifloxacin , Humans , Hydrogen-Ion Concentration , Linear Models , Naphthyridines/analysis , Naphthyridines/blood , Naphthyridines/pharmacokinetics , Reproducibility of Results , Spectrophotometry, Ultraviolet , Tablets, Enteric-Coated , Topoisomerase Inhibitors/analysis , Topoisomerase Inhibitors/blood , Topoisomerase Inhibitors/pharmacokineticsABSTRACT
BACKGROUND/AIMS: the determination of oral bioavailability of drugs which follow nonlinear pharmacokinetics is difficult and few methods are available. In this work, an alternative approach to determine oral bioavailability of voriconazole (VRC), used as a model drug, is presented. METHODS: VRC pharmacokinetics was investigated in Wistar rats after p.o. (40 mg/kg) and i.v. administration (2.5, 5 and 10 mg/kg). VRC elimination showed saturation in all doses investigated, except the lower i.v. dose in which case a 3-compartment model with linear elimination adequately fitted the data. Data for the 2 higher i.v. doses were best described by a 3-compartment model with Michaelis-Menten elimination. A 1-compartment disposition with a saturable metabolic elimination model described the oral profile. VRC absolute oral bioavailability was determined by simultaneous fitting of the i.v. and oral profiles. RESULTS: the Michaelis constant and the maximum velocity estimated after 5 and 10 mg/kg i.v. dosing were 0.54 +/- 0.25 microg/ml and 2.53 +/- 0.54 microg/h, and 0.62 +/- 0.12 microg/ml and 2.74 +/- 0.84 microg/h, respectively. VRC oral bioavailability was determined to be 82.8%. CONCLUSION: the approach presented is an alternative for determining the bioavailability of drugs with similar nonlinear behavior.
