A. Forrest et al., PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL GREPAFLOXACIN IN PATIENTS WITH ACUTE BACTERIAL EXACERBATIONS OF CHRONIC-BRONCHITIS, Journal of antimicrobial chemotherapy, 40, 1997, pp. 45-57
This analysis was designed to characterize the population pharmacokine
tics and pharmacodynamics of oral grepafloxacin (OPC-17,116) in patien
ts with acute bacterial exacerbations of chronic bronchitis (ABECB). T
he study group included 76 patients (43 mate, 33 female) between 23 an
d 81 years of age, who were part of a multicentre, randomized, double-
blind, dos-response study. Patients were randomly assigned to receive
oral regimens of grepafloxacin, 200, 400 or 600 mg, each administered
once daily for 14 days. Plasma samples for drug assay (typically eight
per subject; four samples on either day 3, 4 or 5, plus troughs on ot
her clinic visit days), were obtained during treatment. Population pha
rmacokinetic analysis was accomplished using iterative two-stage analy
sis. Cultures and quantitative Gram stains from serial 24 h collection
s of sputum were used to determine the time (in days) taken to eradica
te each bacterial strain. Population pharmacodynamic analysis was perf
ormed for three measures of antibacterial response: probability of bac
teriological cure, probability of clinical cure, and time to eradicati
on. Grepafloxacin plasma concentration profiles were best fitted by a
pharmacokinetic model with first-order absorption following a lag time
between administration of the dose and onset of systemic absorption.
All three measures of response were strongly related to the 24 h AUIC
(AUC/MIC). At an AUIC of <75, the percent probability of clinical cure
was 71%; at an AUIC of 75-175, it was 80% (P < 0.05) and at an AUIC o
f >175, it was 98% (P < 0.01). In conclusion, antibacterial response f
or grepafloxacin in ABECB patients was highly related to AUIC; values
of <75 appear inadequate and values of >175 were optimal.