Journal of Antimicrobial Chemotherapy, Vol 40, 45-57, Copyright © 1997 by The British Society for Antimicrobial Chemotherapy
A Forrest, S Chodosh, MA Amantea, DA Collins and JJ Schentag
This analysis was designed to characterize the population pharmacokinetics
and pharmacodynamics of oral grepafloxacin (OPC- 17,116) in patients with
acute bacterial exacerbations of chronic bronchitis (ABECB). The study
group included 76 patients (43 male, 33 female) between 23 and 81 years of
age, who were part of a multicentre, randomized, double-blind,
dose-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 other clinic visit
days), were obtained during treatment. Population pharmacokinetic analysis
was accomplished using iterative two-stage analysis. Cultures and
quantitative Gram stains from serial 24 h collections of sputum were used
to determine the time (in days) taken to eradicate each bacterial strain.
Population pharmacodynamic analysis was performed for three measures of
antibacterial response: probability of bacteriological cure, probability of
clinical cure, and time to eradication. 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 of >175, it was 98% (P < 0.01). In
conclusion, antibacterial response for grepafloxacin in ABECB patients was
highly related to AUIC; values of <75 appear inadequate and values of
>175 were optimal.
ORIGINAL ARTICLES
Pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis
SUNY at Buffalo Clinical Pharmacokinetics Laboratory, Millard Fillmore Health System, NY 14209, USA.
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