Gatifloxacin and the elderly: pharmacokinetic-pharmacodynamic rationale for a potential age-related dose reduction

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 AUC(0-24) 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 greater than or equal to65 years from two New Drug Application (NDA) databases were used to estimate AUC(0-24) 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. Results: The mean estimated AUC(0-24) among severe hyperglycaemia cases was 74 mg.h/L (range 57-100). Gatifloxacin AUC(0-24) exposures for the 400 mg regimen were predicted to be higher in patients aged greater than or equal to65 years and similar to the severe hyperglycaemia cases. The probability of AUC(0-24) greater than or equal to60 and greater than or equal to70 in patients aged greater than or equal to65 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 greater than or equal to65 years receiving the 200 mg regimen was 0.99. Conclusions: The probability of a patient aged greater than or equal to65 years having an AUC(0-24) greater than or equal to60-70 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.