title: Convulsant activity and pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of gemifloxacin in rats.
abstract: A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of gemifloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of gemifloxacin at a rate of 4 mg kg of body weight(-1) min(-1) over 50 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. An important delay was observed between concentrations of gemifloxacin in plasma and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site. The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 100 and 200 min. Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied. In conclusion, the successful PK-PD modeling of the gemifloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone.
authors: Department of Pharmaceutical Technology, Bioequivalence Study Centre, Jadavpur University, Kolkata 700 032, India.
authors: Bikash
authors: B
authors: Roy
authors: Anirbandeep
authors: A
authors: Bose
authors: Uttam
authors: U
authors: Bhaumik
authors: Ayan
authors: A
authors: Das
authors: Nilendra
authors: N
authors: Chatterjee
authors: Animesh
authors: A
authors: Ghosh
authors: Soumendra
authors: S
authors: Darbar
authors: Amlan Kanti
authors: AK
authors: Sarkar
authors: Pinaki
authors: P
authors: Sengupta
authors: T K
authors: TK
authors: Pal
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D024841:Fluoroquinolones / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000077735:Gemifloxacin; D008297:Male; D015233:Models, Statistical; D009287:Naphthyridines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced*; D013997:Time Factors; D014202:Tremor / Q000139:chemically induced
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D000077735:Gemifloxacin