JAC Advance Access published online on August 13, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg370
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Division of Infectious
Diseases, Cognigen Corporation, Buffalo, 395 Youngs Road, Buffalo,
NY 14221-5831; University
of the Pacific, School of Health Sciences, Stockton, CA
* Corresponding author. E-mail: paul.ambrose{at}cognigencorp.com.
Received 3 December 2002
; revised 30 May 2003
; accepted 16 June 2003
Objectives: Recently, anecdotal reports
via the FDA's MedWatch reporting system have documented
rare but serious hyperglycaemia in elderly patients receiving gatifloxacin.
One possible factor contributing to these events may be gatifloxacin
overexposure, resulting from age-related decreases in renal function
in elderly patients predisposed to glycaemic alterations. These
analyses examine gatifloxacin exposure in 10 patients with
severe hyperglycaemia, provide a pharmacokinetic-pharmacodynamic
(PK-PD) rationale for a potential age-related dose reduction to
avoid high exposures, and evaluate the likely impact of such a dose
reduction on clinical efficacy in this specific patient population. Methods: First, a previously derived population
pharmacokinetic model, with patient demographics, was used to estimate
gatifloxacin AUC0-24 following a dosage regimen
of 400 mg/24 h in 10 index patients with severe hyperglycaemia.
Second, the population pharmacokinetic model and patient demographic
data from 2696 patients aged Results: The mean estimated AUC0-24 among
severe hyperglycaemia cases was 74 mg•h/L
(range 57-100). Gatifloxacin AUC0-24 exposures
for the 400 mg regimen were predicted to be higher in patients aged Conclusions: The probability of a patient aged
Keywords: hyperglycaemia, pharmacokinetic model, fluoroquinolones
Gatifloxacin and the elderly: pharmacokinetic-pharmacodynamic rationale
for a potential age-related dose reduction
2 Division of Infectious
Diseases, Cognigen Corporation, Buffalo, 395 Youngs Road, Buffalo,
NY 14221-5831; School of Pharmacy and Pharmaceutical Sciences,
University at Buffalo, Buffalo, NY, USA
3 Division of Infectious
Diseases, Cognigen Corporation, Buffalo, 395 Youngs Road, Buffalo,
NY 14221-5831
65 years
from two New Drug Application (NDA) databases were used to estimate
AUC0-24 following dosage regimens for gatifloxacin
of 200 and 400 mg/24 h. Finally, Monte Carlo simulation was utilized
to assess the probability of achieving PK-PD target exposures against Streptococcus pneumoniae in elderly patients using
these regimens.65 years and similar to the severe
hyperglycaemia cases. The probability of AUC0-24 60 and 70
in patients aged 65 years for the 200
mg regimen was 0.03 and <0.01, respectively, versus 0.51
and 0.35 for the 400 mg regimen, respectively. The probability of
achieving PK-PD target exposures against S. pneumoniae in patients
aged 65 years receiving the 200 mg
regimen was 0.99.65 years having an AUC0-24 60-70
mg•h/L is markedly lower following a
200 mg regimen relative to a 400 mg regimen, suggesting a decreased
risk of severe hyperglycaemia in a predisposed patient. Moreover,
a dose reduction does not appear to significantly modify the likelihood of
achieving the PK-PD target of gatifloxacin against S.
pneumoniae.
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